Pharmaceutical compositions for treating cystic fibrosis

ABSTRACT

A pharmaceutical composition comprising Compound I:Methods of treating cystic fibrosis comprising administering one or more of such pharmaceutical compositions to a patient.

This application claims priority to U.S. provisional applications62/626,567, filed Feb. 5, 2018, and 62/657,522, filed Apr. 13, 2018. Thedisclosures of both provisional applications are incorporated herein byreference in their entirety.

One aspect of the invention provides pharmaceutical compositionscomprising modulators of Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR). Cystic fibrosis (CF) is a recessive genetic diseasethat affects approximately 70,000 children and adults worldwide. Despiteprogress in the treatment of CF, there is no cure.

In patients with CF, mutations in CFTR endogenously expressed inrespiratory epithelia lead to reduced apical anion secretion causing animbalance in ion and fluid transport. The resulting decrease in aniontransport contributes to enhanced mucus accumulation in the lung andaccompanying microbial infections that ultimately cause death in CFpatients. In addition to respiratory disease, CF patients typicallysuffer from gastrointestinal problems and pancreatic insufficiency that,if left untreated, result in death. In addition, the majority of maleswith cystic fibrosis are infertile, and fertility is reduced amongfemales with cystic fibrosis.

Sequence analysis of the CFTR gene has revealed a variety of diseasecausing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369;Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989)Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci.USA 87:8447-8451). To date, greater than 2000 mutations in the CF genehave been identified; currently, the CFTR2 database contains informationon only 322 of these identified mutations, with sufficient evidence todefine 281 mutations as disease causing. The most prevalentdisease-causing mutation is a deletion of phenylalanine at position 508of the CFTR amino acid sequence, and is commonly referred to as theF508del mutation. This mutation occurs in approximately 70% of the casesof cystic fibrosis and is associated with severe disease.

The deletion of residue 508 in CFTR prevents the nascent protein fromfolding correctly. This results in the inability of the mutant proteinto exit the endoplasmic reticulum (ER) and traffic to the plasmamembrane. As a result, the number of CFTR channels for anion transportpresent in the membrane is far less than observed in cells expressingwild-type CFTR, i.e., CFTR having no mutations. In addition to impairedtrafficking, the mutation results in defective channel gating. Together,the reduced number of channels in the membrane and the defective gatinglead to reduced anion and fluid transport across epithelia. (Quinton, P.M. (1990), FASEB J. 4: 2709-2727). The channels that are defectivebecause of the F508del mutation are still functional, albeit lessfunctional than wild-type CFTR channels. (Dalemans et al. (1991), NatureLond. 354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50). In addition to F508del, other disease causing mutations inCFTR that result in defective trafficking, synthesis, and/or channelgating could be up- or down-regulated to alter anion secretion andmodify disease progression and/or severity.

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a varietyof cell types, including absorptive and secretory epithelia cells, whereit regulates anion flux across the membrane, as well as the activity ofother ion channels and proteins. In epithelial cells, normal functioningof CFTR is critical for the maintenance of electrolyte transportthroughout the body, including respiratory and digestive tissue. CFTR iscomposed of approximately 1480 amino acids that encode a protein whichis made up of a tandem repeat of transmembrane domains, each containingsix transmembrane helices and a nucleotide binding domain. The twotransmembrane domains are linked by a large, polar, regulatory(R)-domain with multiple phosphorylation sites that regulate channelactivity and cellular trafficking.

Chloride transport takes place by the coordinated activity of ENaC andCFTR present on the apical membrane and the Na⁺—K⁺-ATPase pump and Cl−channels expressed on the basolateral surface of the cell. Secondaryactive transport of chloride from the luminal side leads to theaccumulation of intracellular chloride, which can then passively leavethe cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

Accordingly, there is a need for novel treatments of CFTR mediateddiseases.

Disclosed herein are pharmaceutical compositions comprising Compound Iand/or pharmaceutically acceptable salts thereof, Compound II and/orpharmaceutically acceptable salts thereof, and Compound III-d orCompound III and/or pharmaceutically acceptable salts thereof. CompoundI can be depicted as having the following structure:

A chemical name for Compound I isN-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide.PCT Application No. PCT/US2017/065425, incorporated herein by reference,discloses Compound I, a method of making Compound I, a method of makingForm A of Compound I, and that Compound I is a CFTR modulator with anEC₅₀ of 0.07 μM. In some embodiments, Compound I is amorphous.

In some embodiments, Compound I is Form A. In some embodiments,crystalline Form A is characterized by an X-ray powder diffractogramhaving a signal at least one two-theta value chosen from 6.6±0.2,7.6±0.2, 9.6±0.2, 12.4±0.2, 13.1±0.2, 15.2±0.2, 16.4±0.2, 18.2±0.2, and18.6±0.2. In some embodiments, crystalline Form A is characterized by anX-ray powder diffractogram having a signal at at least three two-thetavalues chosen from 6.6±0.2, 7.6±0.2, 9.6±0.2, 12.4±0.2, 13.1±0.2,15.2±0.2, 16.4±0.2, 18.2±0.2, and 18.6±0.2. In some embodiments,crystalline Form A is characterized by an X-ray powder diffractographhaving a signal at at least three two-theta values chosen from 6.6±0.2,9.6±0.2, 13.1±0.2, 15.2±0.2, 18.2±0.2, and 18.6±0.2. In someembodiments, crystalline Form A is characterized by an X-ray powderdiffractograph having a signal at three two-theta values of 6.6±0.2,13.1±0.2, 18.2±0.2. In some embodiments, crystalline Form A ischaracterized by an X-ray powder diffractograph having a signal at sixtwo-theta values of 6.6±0.2, 9.6±0.2, 13.1±0.2, 15.2±0.2, 18.2±0.2, and18.6±0.2. In some embodiments, Crystalline Form A is characterized by anX-ray powder diffractogram substantially similar to that in FIG. 4A. Insome embodiments, Crystalline Form A is characterized by an X-ray powderdiffractogram substantially similar to that in FIG. 4B. Crystalline FormA was found to be the most thermodynamically stable form and to providegood bioavailability.

Compound II can be depicted as having the following structure:

A chemical name for Compound II is(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide;

Compound III-d can be depicted as having the following structure:

A chemical name for Compound III-d isN-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;

Compound III can be depicted as having the following structure:

A chemical name for Compound III isN-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-1H is a representative list of CFTR genetic mutations.

FIG. 2A is dissolution data for Compound I.

FIG. 2B is dissolution data for Compound II.

FIG. 2C is dissolution data for Compound III-d.

FIG. 3A shows bioavailability of Compound I for Tablet 1, Tablet 2, andTablet 3 in a dog.

FIG. 3B shows bioavailability of Compound II for Tablet 1, Tablet 2, andTablet 3 in a dog.

FIG. 3C shows bioavailability of Compound III-d for Tablet 1, Tablet 2,and Tablet 3 in a dog.

FIG. 4A is an XRPD of Form A of Compound 1.

FIG. 4B is an XRPD of a tablet with the composition of Tablet 4.

FIG. 5A is dissolution data for Compound I in Tablet 4.

FIG. 5B is dissolution data for Compound II in Tablet 4.

FIG. 5C is dissolution data for Compound III in Tablet 4.

FIG. 6A is dissolution data for Compound I in Tablet 14.

FIG. 6B is dissolution data for Compound II in Tablet 14.

FIG. 6C is dissolution data for Compound III in Tablet 14.

DEFINITIONS

As used herein, “CFTR” means cystic fibrosis transmembrane conductanceregulator.

As used herein, “mutations” can refer to mutations in the CFTR gene orthe CFTR protein. A “CFTR gene mutation” refers to a mutation in theCFTR gene, and a “CFTR protein mutation” refers to a mutation in theCFTR protein. A genetic defect or mutation, or a change in thenucleotides in a gene in general results in a mutation in the CFTRprotein translated from that gene, or a frame shift(s).

The term “F508del” refers to a mutant CFTR protein which is lacking theamino acid phenylalanine at position 508.

As used herein, a patient who is “homozygous” for a particular genemutation has the same mutation on each allele.

As used herein, a patient who is “heterozygous” for a particular genemutation has this mutation on one allele, and a different mutation onthe other allele.

As used herein, the term “modulator” refers to a compound that increasesthe activity of a biological compound such as a protein. For example, aCFTR modulator is a compound that increases the activity of CFTR. Theincrease in activity resulting from a CFTR modulator includes but is notlimited to compounds that correct, potentiate, stabilize and/or amplifyCFTR.

As used herein, the term “CFTR corrector” refers to a compound thatfacilitates the processing and trafficking of CFTR to increase theamount of CFTR at the cell surface. Compound I, Compound II, and theirpharmaceutically acceptable salts thereof disclosed herein are CFTRcorrectors.

As used herein, the term “CFTR potentiator” refers to a compound thatincreases the channel activity of CFTR protein located at the cellsurface, resulting in enhanced ion transport. Compound III-d andCompound III disclosed herein are CFTR potentiators.

As used herein, the term “active pharmaceutical ingredient” (“API”)refers to a biologically active compound.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt form of a compound of this disclosure wherein the salt is nontoxic.Pharmaceutically acceptable salts of the compounds of this disclosureinclude those derived from suitable inorganic and organic acids andbases. Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts are, for example, thosedisclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66,1-19. For example, Table 1 of that article provides the followingpharmaceutically acceptable salts:

TABLE 1 Acetate Iodide Benzathine Benzenesulfonate IsethionateChloroprocaine Benzoate Lactate Choline Bicarbonate LactobionateDiethanolamine Bitartrate Malate Ethylenediamine Bromide MaleateMeglumine Calcium edetate Mandelate Procaine Camsylate Mesylate AluminumCarbonate Methylbromide Calcium Chloride Methylnitrate Lithium CitrateMethylsulfate Magnesium Dihydrochloride Mucate Potassium EdetateNapsylate Sodium Edisylate Nitrate Zinc Estolate Pamoate (Embonate)Esylate Pantothenate Fumarate Phosphate/diphosphate GluceptatePolygalacturonate Gluconate Salicylate Glutamate StearateGlycollylarsanilate Subacetate Hexylresorcinate Succinate HydrabamineSulfate Hydrobromide Tannate Hydrochloride Tartrate HydroxynaphthoateTeociate Triethiodide

Non-limiting examples of pharmaceutically acceptable acid addition saltsinclude: salts formed with inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid;salts formed with organic acids, such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acid;and salts formed by using other methods used in the art, such as ionexchange. Non-limiting examples of pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.Pharmaceutically acceptable salts derived from appropriate bases includealkali metal, alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ salts.This disclosure also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Suitablenon-limiting examples of alkali and alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium. Further non-limitingexamples of pharmaceutically acceptable salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and aryl sulfonate. Other suitable, non-limiting examples ofpharmaceutically acceptable salts include besylate and glucosaminesalts.

As used herein, the term “XRPD” refers to the analyticalcharacterization method of X-ray powder diffraction. XRPD patterns canbe recorded at ambient conditions in transmission or reflection geometryusing a diffractometer.

As used herein, the terms “X-ray powder diffractogram,” “X-ray powderdiffraction pattern,” “XRPD pattern” interchangeably refer to anexperimentally obtained pattern plotting signal positions (on theabscissa) versus signal intensities (on the ordinate). For an amorphousmaterial, an X-ray powder diffractogram may include one or more broadsignals; and for a crystalline material, an X-ray powder diffractogrammay include one or more signals, each identified by its angular value asmeasured in degrees 2θ (°2θ), depicted on the abscissa of an X-raypowder diffractogram, which may be expressed as “a signal at . . .degrees two-theta,” “a signal at [a] two-theta value(s) of . . . ”and/or “a signal at at least . . . two-theta value(s) chosen from . . ..”

A “signal” or “peak” as used herein refers to a point in the XRPDpattern where the intensity as measured in counts is at a local. One ofordinary skill in the art would recognize that one or more signals (orpeaks) in an XRPD pattern may overlap and may, for example, not beapparent to the naked eye. Indeed, one of ordinary skill in the artwould recognize that some art-recognized methods are capable of andsuitable for determining whether a signal exists in a pattern, such asRietveld refinement.

As used herein, “a signal at . . . degrees two-theta,” “a signal at [a]two-theta value[ ] of . . . ” and/or “a signal at at least . . .two-theta value(s) chosen from . . . ” refer to X-ray reflectionpositions as measured and observed in X-ray powder diffractionexperiments (°2θ).

The repeatability of the angular values is in the range of ±0.2° 2θ,i.e., the angular value can be at the recited angular value +0.2 degreestwo-theta, the angular value −0.2 degrees two-theta, or any valuebetween those two end points (angular value +0.2 degrees two-theta andangular value −0.2 degrees two-theta).

The terms “signal intensities” and “peak intensities” interchangeablyrefer to relative signal intensities within a given X-ray powderdiffractogram. Factors that can affect the relative signal or peakintensities include sample thickness and preferred orientation (e.g.,the crystalline particles are not distributed randomly).

The term “X-ray powder diffractogram having a signal at . . . two-thetavalues” as used herein refers to an XRPD pattern that contains X-rayreflection positions as measured and observed in X-ray powderdiffraction experiments (°2θ).

As used herein, an X-ray powder diffractogram is “substantially similarto that in [a particular] Figure” when at least 90%, such as at least95%, at least 98%, or at least 99%, of the signals in the twodiffractograms overlap. In determining “substantial similarity,” one ofordinary skill in the art will understand that there may be variation inthe intensities and/or signal positions in XRPD diffractograms even forthe same crystalline form. Thus, those of ordinary skill in the art willunderstand that the signal maximum values in XRPD diffractograms (indegrees two-theta (°2θ) referred to herein) generally mean that valuereported ±0.2 degrees 2θ of the reported value, an art-recognizedvariance.

As used herein, a crystalline form is “substantially pure” when itaccounts for an amount by weight equal to or greater than 90% of the sumof all solid form(s) in a sample as determined by a method in accordancewith the art, such as quantitative XRPD. In some embodiments, the solidform is “substantially pure” when it accounts for an amount by weightequal to or greater than 95% of the sum of all solid form(s) in asample. In some embodiments, the solid form is “substantially pure” whenit accounts for an amount by weight equal to or greater than 99% of thesum of all solid form(s) in a sample.

As used herein, the term “amorphous” refers to a solid material havingno long range order in the position of its molecules. Amorphous solidsare generally supercooled liquids in which the molecules are arranged ina random manner so that there is no well-defined arrangement, e.g.,molecular packing, and no long range order. For example, an amorphousmaterial is a solid material having no sharp characteristic crystallinepeak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is notcrystalline as determined by XRPD). Instead, one or more broad peaks(e.g., halos) appear in its XRPD pattern. Broad peaks are characteristicof an amorphous solid. See, e.g., US 2004/0006237 for a comparison ofXRPDs of an amorphous material and crystalline material.

As used herein, the term “substantially amorphous” refers to a solidmaterial having little or no long range order in the position of itsmolecules. For example, substantially amorphous materials have less than15% crystallinity (e.g., less than 10% crystallinity or less than 5%crystallinity). It is also noted that the term ‘substantially amorphous’includes the descriptor, ‘amorphous’, which refers to materials havingno (0%) crystallinity.

As used herein, the term “dispersion” refers to a disperse system inwhich one substance, the dispersed phase, is distributed, in discreteunits, throughout a second substance (the continuous phase or vehicle).The size of the dispersed phase can vary considerably (e.g. colloidalparticles of nanometer dimension, to multiple microns in size). Ingeneral, the dispersed phases can be solids, liquids, or gases. In thecase of a solid dispersion, the dispersed and continuous phases are bothsolids. In pharmaceutical applications, a solid dispersion can include acrystalline drug (dispersed phase) in an amorphous polymer (continuousphase); or alternatively, an amorphous drug (dispersed phase) in anamorphous polymer (continuous phase). In some embodiments, a soliddispersion includes the polymer constituting the dispersed phase, andthe drug constituting the continuous phase. Or, a solid dispersionincludes the drug constituting the dispersed phase, and the polymerconstituting the continuous phase.

The terms “patient” and “subject” are used interchangeably and refer toan animal including humans.

The terms “effective dose” and “effective amount” are usedinterchangeably herein and refer to that amount of a compound thatproduces the desired effect for which it is administered (e.g.,improvement in CF or a symptom of CF, or lessening the severity of CF ora symptom of CF). The exact amount of an effective dose will depend onthe purpose of the treatment, and will be ascertainable by one skilledin the art using known techniques (see, e.g., Lloyd (1999) The Art,Science and Technology of Pharmaceutical Compounding).

As used herein, the terms “treatment,” “treating,” and the likegenerally mean the improvement of CF or its symptoms or lessening theseverity of CF or its symptoms in a subject. “Treatment,” as usedherein, includes, but is not limited to, the following: increased growthof the subject, increased weight gain, reduction of mucus in the lungs,improved pancreatic and/or liver function, reduction of chestinfections, and/or reductions in coughing or shortness of breath.Improvements in or lessening the severity of any of these symptoms canbe readily assessed according to standard methods and techniques knownin the art.

As used herein, the term “in combination with,” when referring to two ormore compounds, agents, or additional active pharmaceutical ingredients,means the administration of two or more compounds, agents, or activepharmaceutical ingredients to the patient prior to, concurrent with, orsubsequent to each other.

The term “approximately”, when used in connection with doses, amounts,or weight percent of ingredients of a composition or a dosage form,include the value of a specified dose, amount, or weight percent or arange of the dose, amount, or weight percent that is recognized by oneof ordinary skill in the art to provide a pharmacological effectequivalent to that obtained from the specified dose, amount, or weightpercent.

Pharmaceutical Compositions

Disclosed herein is a pharmaceutical composition comprising a firstsolid dispersion and a second solid dispersion, wherein thepharmaceutical composition comprises

(a) 25 mg to 250 mg of Compound I:

(b) a first solid dispersion comprising 20 mg to 150 mg of Compound II:

-   -   and 10 wt % to 30 wt % of a polymer relative to the total weight        of the first solid dispersion; and    -   (c) a second solid dispersion comprising 25 mg to 200 mg of        Compound III-d:

-   -   Compound III:

-   -   and 10 wt % to 30 wt % of a polymer relative to the total weight        of the second solid dispersion. In some embodiments, the        pharmaceutical composition is a single tablet

In some embodiments, each of Compound II and Compound III-d isindependently substantially amorphous. In some embodiments, each ofCompound II and Compound III-d is independently crystalline. In someembodiments, each of Compound II and Compound III-d or Compound III isindependently a mixture of forms (crystalline and/or amorphous).

Solid Dispersions

In some embodiments, the pharmaceutical compositions (e.g., tablets)disclosed herein comprise a first solid dispersion comprising CompoundII and a second solid dispersion comprising Compound III-d or CompoundIII.

In some embodiments, each of the first and second solid dispersionsindependently comprise a plurality of particles having a mean particlediameter of 5 to 100 microns. In some embodiments, each of the first andsecond solid dispersions independently comprise a plurality of particleshaving a mean particle diameter of 15 to 40 microns. In someembodiments, each of the first and second solid dispersionsindependently comprise a plurality of particles having a mean particlediameter of 15 microns.

In some embodiments, the first solid dispersions and the first spraydried dispersions of the disclosure independently comprise substantiallyamorphous Compound II. In some embodiments, the second solid dispersionsand the second spray dried dispersions of the disclosure independentlycomprises substantially amorphous Compound III-d or Compound III.

In some embodiments, the solid dispersions and the spray drieddispersions of the disclosure can comprise other excipients, such aspolymers and/or surfactants. Any suitable polymers and surfactants knownin the art can be used in the disclosure. Certain exemplary polymers andsurfactants are as described below.

Solid dispersions of any one of Compounds II, III-d, or III may beprepared by any suitable method known in the art, e.g., spray drying,lyophilizing, hot melting, or cyrogrounding/cryomilling techniques. Forexample, see WO2015/160787. Typically such spray drying, lyophilizing,hot melting or cyrogrounding/cryomilling techniques generates anamorphous form of API (e.g., Compounds II, III-d, or III).

Spray drying is a process that converts a liquid feed to a driedparticulate form. Optionally, a secondary drying process such asfluidized bed drying or vacuum drying may be used to reduce residualsolvents to pharmaceutically acceptable levels. Typically, spray dryinginvolves contacting a highly dispersed liquid suspension or solution,and a sufficient volume of hot gas to produce evaporation and drying ofthe liquid droplets. The preparation to be spray dried can be anysolution, coarse suspension, slurry, colloidal dispersion, or paste thatmay be atomized using the selected spray drying apparatus. In oneprocedure, the preparation is sprayed into a current of warm filteredgas that evaporates the solvent and conveys the dried product to acollector (e.g. a cyclone). The spent gas is then exhausted with thesolvent, or alternatively the spent air is sent to a condenser tocapture and potentially recycle the solvent. Commercially availabletypes of apparatus may be used to conduct the spray drying. For example,commercial spray dryers are manufactured by Buchi Ltd. And Niro (e.g.,the PSD line of spray driers manufactured by Niro) (see, US2004/0105820; US 2003/0144257).

Techniques and methods for spray drying may be found in Perry's ChemicalEngineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney,eds.), McGraw-Hill book co. (1984); and Marshall “Atomization andSpray-Drying” 50, Chem. Eng. Prog. Monogr. Series 2 (1954).

Removal of the solvent may require a subsequent drying step, such astray drying, fluid bed drying, vacuum drying, microwave drying, rotarydrum drying or biconical vacuum drying.

In one embodiment, the solid dispersions and the spray dried dispersionsof the disclosure are fluid bed dried.

In one process, the solvent includes a volatile solvent, for example asolvent having a boiling point of less than 100° C. In some embodiments,the solvent includes a mixture of solvents, for example a mixture ofvolatile solvents or a mixture of volatile and non-volatile solvents.Where mixtures of solvents are used, the mixture can include one or morenon-volatile solvents, for example, where the non-volatile solvent ispresent in the mixture at less than 15%, e.g., less than 12%, less than10%, less than 8%, less than 5%, less than 3%, or less than 2%.

In some processes, solvents are those solvents where the API(s) (e.g.,Compound II and/or Compound III-d and/or Compound III) has solubilitiesof at least 10 mg/ml, (e.g., at least 15 mg/ml, 20 mg/ml, 25 mg/ml, 30mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, or greater). In otherprocesses, solvents include those solvents where the API(s) (e.g.,Compound II and/or Compound III-d and/or Compound III) has a solubilityof at least 20 mg/ml.

Exemplary solvents that could be tested include acetone, cyclohexane,dichloromethane or methylene chloride (DCM), N,N-dimethylacetamide(DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone(DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether,glacial acetic acid (HAc), methyl ethyl ketone (MEK),N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE),tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol,isopropyl alcohol, isopropyl acetate, and toluene. Exemplary co-solventsinclude DCM/methanol, acetone/DMSO, acetone/DMF, acetone/water,MEK/water, THF/water, dioxane/water. In a two solvent system, thesolvents can be present from 0.1% to 99.9% w/w. In some preferredembodiments, water is a co-solvent with acetone where water is presentfrom 0.1% to 15%, for example 9% to 11%, e.g., 10%. In some preferredembodiments, water is a co-solvent with MEK where water is present from0.1% to 15%, for example 9% to 11%, e.g., 10%. In some embodiments thesolvent system includes three solvents. Certain exemplary solventsinclude those described above, for example, MEK, DCM, water, methanol,IPA, and mixtures thereof.

The particle size and the temperature drying range may be modified toprepare an optimal solid dispersion. As would be appreciated by skilledpractitioners, a small particle size would lead to improved solventremoval. Applicants have found however, that smaller particles mayresult in low bulk density that, under some circumstances do not provideoptimal solid dispersions for downstream processing such as tableting.

A solid dispersion (e.g., a spray dried dispersion) disclosed herein mayoptionally include a surfactant. A surfactant or surfactant mixturewould generally decrease the interfacial tension between the soliddispersion and an aqueous medium. An appropriate surfactant orsurfactant mixture may also enhance aqueous solubility andbioavailability of the API(s) (e.g., Compound II and/or Compound III-dand/or Compound III) from a solid dispersion. The surfactants for use inconnection with the disclosure include, but are not limited to, sorbitanfatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acidesters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodiumdodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusatesodium), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate,Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), SodiumN-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate,Sodium Palmitate, Gelucire 44/14, ethylenediamine tetraacetic acid(EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate(TPGS), Lecithin, Glutanic acid monosodium monohydrate, Labrasol, PEG 8caprylic/capric glycerides, Transcutol, diethylene glycol monoethylether, Solutol HS-15, polyethylene glycol/hydroxystearate, TaurocholicAcid, Pluronic F68, Pluronic F108, and Pluronic F127 (or any otherpolyoxyethylene-polyoxypropylene co-polymers (Pluronics®) or saturatedpolyglycolized glycerides (Gelucirs®)). Specific examples of suchsurfactants that may be used in connection with this disclosure include,but are not limited to, Span 65, Span 25, Tween 20, Capryol 90, PluronicF108, sodium lauryl sulfate (SLS), Vitamin E TPGS, pluronics andcopolymers.

In some embodiments, SLS is used as a surfactant in the solid dispersionof Compound III-d and/or III.

The amount of the surfactant (e.g., SLS) relative to the total weight ofthe solid dispersion may be between 0.1-15% w/w. For example, it is from0.5% to 10%, such as from 0.5 to 5%, e.g., 0.5 to 4%, 0.5 to 3%, 0.5 to2%, 0.5 to 1%, or 0.5%.

In certain embodiments, the amount of the surfactant relative to thetotal weight of the solid dispersion is at least 0.1% or at least 0.5%.In these embodiments, the surfactant would be present in an amount of nomore than 15%, or no more than 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2% or 1%. In some embodiments, the surfactant is in an amount of0.5% by weight.

Candidate surfactants (or other components) can be tested forsuitability for use in the disclosure in a manner similar to thatdescribed for testing polymers.

One aspect of the disclosure provides a method of generating a spraydried dispersion comprising (i) providing a mixture of one or more APIsand a solvent; and (ii) forcing the mixture through a nozzle andsubjecting the mixture to spray drying conditions to generate the spraydried dispersion.

Another aspect of the disclosure provides a method of generating a spraydried dispersion comprising: (i) providing a mixture comprising one ormore APIs and a solvent(s); and (ii) forcing the mixture out of a nozzleunder spray drying conditions to generate a spray dried dispersion.

Another aspect of the disclosure provides a method of generating a spraydried dispersion comprising (i) spraying a mixture through a nozzle,wherein the mixture comprises one or more APIs and a solvent; and (ii)forcing the mixture through a nozzle under spray drying conditions togenerate a particle that comprises the APIs.

Another aspect of the disclosure provides a spray dried dispersioncomprising one or more APIs, wherein the dispersion is substantiallyfree of a polymer, and wherein the spray dried dispersion is generatedby (i) providing a mixture that consists essentially of one or more APIsand a solvent; and (ii) forcing the mixture through a nozzle under spraydrying conditions to generate the spray dried dispersion.

Another aspect of the disclosure provides a spray dried dispersioncomprising one or more APIs, wherein the dispersion is generated by (i)providing a mixture that comprising one or more APIs, a polymer(s), anda solvent(s); and (ii) forcing the mixture through a nozzle under spraydrying conditions to generate the spray dried dispersion.

Another aspect of the disclosure provides a spray dried dispersioncomprising a particle, wherein the particle comprises one or more APIsand a polymer(s), and wherein the spray dried dispersion is generated by(i) spraying a mixture through a nozzle, wherein the mixture comprisesone or more APIs and a solvent; and (ii) forcing the mixture through anozzle under spray drying conditions to generate the spray drieddispersion.

Another aspect of the disclosure provides a spray dried dispersioncomprising a particle, wherein the particle comprises one or more APIs,and the particle is substantially free of a polymer, and wherein thespray dried dispersion is generated by (i) spraying a mixture through anozzle, wherein the mixture comprises one or more APIs and a solvent;and (ii) forcing the mixture through a nozzle under spray dryingconditions to generate the spray dried dispersion.

In some embodiments, the one or more APIs are selected from Compound II,Compound III-d, and Compound III.

Some embodiments further comprise further drying the spray drieddispersion. For example, the spray dried dispersion is dried underreduced pressure. In other examples, the spray dried dispersion is driedat a temperature of from 50° C. to 100° C.

In some embodiments, the solvent comprises a polar organic solvent.Examples of polar organic solvents include methylethyl ketone, THF, DCM,methanol, or IPA, or any combination thereof, such as, for exampleDCM/methanol. In other examples, the solvent further comprises water.For instance, the solvent could be methylethyl ketone/water, THF/water,or methylethyl ketone/water/IPA. For example, the ratio of the polarorganic solvent to water is from 70:30 to 95:5 by volume. In otherinstances, the ratio of the polar organic solvent to water is 90:10 byvolume.

Some embodiments further comprise filtering the mixture before it isforced through the nozzle. Such filtering can be accomplished using anysuitable filter media having a suitable pore size.

Some embodiments further comprise applying heat to the mixture as itenters the nozzle. This heating can be accomplished using any suitableheating element.

In some embodiments, the nozzle comprises an inlet and an outlet, andthe inlet is heated to a temperature that is less than the boiling pointof the solvent.

In some embodiments, the mixture is forced through the nozzle by apressurized gas. Examples of suitable pressurized gases include thosepressurized gas that are inert to the first agent, the second agent, andthe solvent. In one example, the pressurized gas comprises elementalnitrogen.

In some embodiments, the pressurized gas has a positive pressure of from90 psi to 150 psi.

In some embodiments, a pharmaceutically acceptable composition of thedisclosure comprising substantially amorphous API(s) (e.g., Compound II,Compound III-d, and Compound III) may be prepared by non-spray dryingtechniques, such as, for example, cyrogrounding/cryomilling techniques.A composition comprising substantially amorphous API(s) (e.g., CompoundII, Compound III-d, and Compound III) may also be prepared by hot meltextrusion techniques.

In some embodiments, the solid dispersions (e.g., spray drieddispersions) of the disclosure comprise a polymer(s). Any suitablepolymers known in the art can be used in the disclosure. Exemplarysuitable polymers include polymers selected from cellulose-basedpolymers, polyoxyethylene-based polymers, polyethylene-propylene glycolcopolymers, vinyl-based polymers, PEO-polyvinyl caprolactam-basedpolymers, and polymethacrylate-based polymers.

The cellulose-based polymers include a methylcellulose, a hydroxypropylmethylcellulose (HPMC) (hypromellose), a hypromellose phthalate(HPMC-P), a hypromellose acetate succinate, and co-polymers thereof. Thepolyoxyethylene-based polymers include a polyethylene-propylene glycol,a polyethylene glycol, a poloxamer, and co-polymers thereof. Thevinyl-based polymers include a polyvinylpyrrolidine (PVP), and PVP/VA.The PEO-polyvinyl caprolactam-based polymers include a polyethyleneglycol, polyvinyl acetate and polyvinylcaprolactame-based graftcopolymer (e.g., Soluplus®). The polymethacrylate-based polymers aresynthetic cationic and anionic polymers of dimethylaminoethylmethacrylates, methacrylic acid, and methacrylic acid esters in varyingratios. Several types are commercially available and may be obtained asthe dry powder, aqueous dispersion, or organic solution. Examples ofsuch polymethacrylate-based polymers include a poly(methacrylic acid,ethyl acrylate) (1:1), a dimethylaminoethylmethacrylate-methylmethacrylate copolymer, and an Eudragit®.

In some embodiments, the cellulose-based polymer is a hypromelloseacetate succinate (also known as hydroxypropyl methylcellulose acetatesuccinate or HMPCAS) and a hypromellose (also known as hydroxypropylmethylcellulose or HPMC), or a combination of hypromellose acetatesuccinate and a hypromellose. HPMCAS is available in various gradesbased on the content of acetyl and succinoyl groups (wt %) in the HPMCASmolecule and on particle size. For example, HPMCAS grades L, M, and Hare available. HPMCAS-H is a grade that contains about 10-14 wt % ofacetyl groups and about 4-8 wt % of succinoyl groups. Each HPMCAS gradeis available in two particle sizes, F (fine) and G (granular). HPMCcomes in various types (for example, HPMC E, F, J, and K-types). HPMC Etype means that there are about 28-30% methoxy groups and about 7-12%hydroxypropoxy groups. There are various E grades ranging from low tohigh viscosity. For example, E3 means the viscosity is about 2.4-3.6millipascal seconds (mPa·s) for HPMC measured at 2% in water at 20° C.;E15 means the viscosity is about 12-18 mPa·s for the HPMC measured at 2%in water at 20° C.; and E50 means the viscosity is about 40-60 mPa·s forthe HPMC measured at 2% in water at 20° C.

In some embodiments, the cellulose-based polymer is a hypromelloseacetate succinate and a hypromellose, or a combination of hypromelloseacetate succinate and a hypromellose.

In some embodiments, the cellulose-based polymer is hypromellose E15,hypromellose acetate succinate L or hypromellose acetate succinate H.

In some embodiments, the polyoxyethylene-based polymer orpolyethylene-propylene glycol copolymer is a polyethylene glycol or apluronic.

In some embodiments, the polyoxyethylene-based polymer orpolyethylene-propylene glycol copolymer is polyethylene glycol 3350 orpoloxamer 407.

In some embodiments, the vinyl-based polymer is avinylpolyvinylpyrrolidine-based polymer, such as polyvinylpyrrolidineK30 or polyvinylpyrrolidine VA 64.

In some embodiments, the polymethacrylate polymer is Eudragit L100-55 orEudragit® E PO.

In some embodiments, the polymer(s) is selected from cellulosic polymerssuch as HPMC and/or HPMCAS.

In one embodiment, a polymer is able to dissolve in aqueous media. Thesolubility of the polymers may be pH independent or pH dependent. Thelatter include one or more enteric polymers. The term “enteric polymer”refers to a polymer that is preferentially soluble in the less acidicenvironment of the intestine relative to the more acid environment ofthe stomach, for example, a polymer that is insoluble in acidic aqueousmedia but soluble when the pH is above 5-6. An appropriate polymer ischemically and biologically inert. In order to improve the physicalstability of the solid dispersions, the glass transition temperature(Tg) of the polymer is as high as possible. For example, polymers thathave a glass transition temperature at least equal to or greater thanthe glass transition temperature of the API. Other polymers have a glasstransition temperature that is within 10 to 15° C. of the API.

Additionally, the hygroscopicity of the polymers is as low, e.g., lessthan 10%. For the purpose of comparison in this application, thehygroscopicity of a polymer or composition is characterized at 60%relative humidity. In some preferred embodiments, the polymer has lessthan 10% water absorption, for example less than 9%, less than 8%, lessthan 7%, less than 6%, less than 5%, less than 4%, less than 3%, or lessthan 2% water absorption. The hygroscopicity can also affect thephysical stability of the solid dispersions. Generally, moistureadsorbed in the polymers can greatly reduce the Tg of the polymers aswell as the resulting solid dispersions, which will further reduce thephysical stability of the solid dispersions as described above.

In one embodiment, the polymer is one or more water-soluble polymer(s)or partially water-soluble polymer(s). Water-soluble or partiallywater-soluble polymers include but are not limited to, cellulosederivatives (e.g., hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones(PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates,such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g.,β-cyclodextrin) and copolymers and derivatives thereof, including forexample PVP-VA (polyvinylpyrollidone-vinyl acetate).

In some embodiments, the polymer is hydroxypropylmethylcellulose (HPMC),such as HPMC E50, HPMC E15, or HPMC E3.

As discussed herein, the polymer can be a pH-dependent enteric polymer.Such pH-dependent enteric polymers include, but are not limited to,cellulose derivatives (e.g., cellulose acetate phthalate (CAP)),hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or asalt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetatetrimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP),hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), andmethylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g.,Eudragit® S). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymeris hydroxypropyl methyl cellulose acetate succinate HG grade(HPMCAS-HG).

In yet another embodiment, the polymer is a polyvinylpyrrolidoneco-polymer, for example, a vinylpyrrolidone/vinyl acetate co-polymer(PVP/VA).

In embodiments where Compound II, Compound III-d, or Compound III formsa solid dispersion with a polymer, for example with an HPMC, HPMCAS, orPVP/VA polymer, the amount of polymer relative to the total weight ofthe solid dispersion ranges from 0.1% to 99% by weight. Unless otherwisespecified, percentages of drug, polymer and other excipients asdescribed within a dispersion are given in weight percentages. Theamount of polymer is typically at least 20%, and preferably at least30%, for example, at least 35%, at least 40%, at least 45%, or 50%(e.g., 49.5%). The amount is typically 99% or less, and preferably 80%or less, for example 75% or less, 70% or less, 65% or less, 60% or less,or 55% or less. In one embodiment, the polymer is in an amount of up to50% of the total weight of the dispersion (and even more specifically,between 40% and 50%, such as 49%, 49.5%, or 50%).

In some embodiments, the API (e.g., Compound II, Compound III-d, orCompound III) and polymer are present in roughly equal amounts inweight, for example each of the polymer and the drug make up half of thepercentage weight of the dispersion. For example, the polymer is presentin 49.5 wt % and Compound II, Compound III-d, or Compound III is presentin 50 wt %. In another embodiment Compound II, Compound III-d, orCompound III is present in an amount greater than half of the percentageweight of the dispersions. For example, the polymer is present in 20 wt% and Compound II, Compound III-d, or Compound III is present in 80 wt%. In other embodiments, the polymer is present in 19.5 wt % andCompound II, Compound III-d, or Compound III is present in 80 wt %.

In some embodiments, the API (e.g., Compound II, Compound III-d, orCompound III) and the polymer combined represent 1% to 20% w/w totalsolid content of the spray drying solution prior to spray drying. Insome embodiments, Compound II, Compound III-d, or Compound III, and thepolymer combined represent 5% to 15% w/w total solid content of thespray drying solution prior to spray drying. In some embodiments,Compound II, Compound III-d, or Compound III and the polymer combinedrepresent 11% w/w total solid content of the spray drying solution priorto spray drying.

In some embodiments, the dispersion further includes other minoringredients, such as a surfactant (e.g., SLS). In some embodiments, thesurfactant is present in less than 10% of the dispersion, for exampleless than 9%, less than 8%, less than 7%, less than 6%, less than 5%,less than 4%, less than 3%, less than 2%, 1%, or 0.5%.

In embodiments including a polymer, the polymer is present in an amounteffective for stabilizing the solid dispersion. Stabilizing includesinhibiting or preventing, the crystallization of an API (e.g., CompoundII, Compound III-d, or Compound III). Such stabilizing would inhibit theconversion of the API from amorphous to crystalline form. For example,the polymer would prevent at least a portion (e.g., 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or greater) ofthe API from converting from an amorphous to a crystalline form.Stabilization can be measured, for example, by measuring the glasstransition temperature of the solid dispersion, measuring the amount ofcrystalline material, measuring the rate of relaxation of the amorphousmaterial, or by measuring the solubility or bioavailability of the API.

In some embodiments, the polymers for use in the disclosure have a glasstransition temperature of no less than 10-15° C. lower than the glasstransition temperature of API. In some instances, the glass transitiontemperature of the polymer is greater than the glass transitiontemperature of API, and in general at least 50° C. higher than thedesired storage temperature of the drug product. For example, at least100° C., at least 105° C., at least 105° C., at least 110° C., at least120° C., at least 130° C., at least 140° C., at least 150° C., at least

160° C., at least 160° C., or greater.

In some embodiments, the polymers for use in the disclosure have similaror better solubility in solvents suitable for spray drying processesrelative to that of an API (e.g., Compound II, Compound III-d, orCompound III). In some embodiments, the polymer will dissolve in one ormore of the same solvents or solvent systems as the API.

In some embodiments, the polymers for use in the disclosure can increasethe solubility of an API (e.g., Compound II, Compound III-d, or CompoundIII) in aqueous and physiologically relative media either relative tothe solubility of the API in the absence of polymer or relative to thesolubility of the API when combined with a reference polymer. Forexample, the polymers can increase the solubility of Compound II,Compound III-d, or Compound III by reducing the amount of amorphousCompound II, Compound III-d, or Compound III that converts to acrystalline form(s), either from a solid amorphous dispersion or from aliquid suspension.

In some embodiments, the polymers for use in the disclosure can decreasethe relaxation rate of the amorphous substance.

In some embodiments, the polymers for use in the disclosure can increasethe physical and/or chemical stability of an API (e.g., Compound II,Compound III-d, or Compound III).

In some embodiments, the polymers for use in the disclosure can improvethe manufacturability of an API (e.g., Compound II, Compound III-d, orCompound III).

In some embodiments, the polymers for use in the disclosure can improveone or more of the handling, administration or storage properties of anAPI (e.g., Compound II, Compound III-d, or Compound III).

In some embodiments, the polymers for use in the disclosure have littleor no unfavorable interaction with other pharmaceutical components, forexample excipients.

The suitability of a candidate polymer (or other component) can betested using the spray drying methods (or other methods) describedherein to form an amorphous composition. The candidate composition canbe compared in terms of stability, resistance to the formation ofcrystals, or other properties, and compared to a reference preparation,e.g., a preparation of neat amorphous Compound I, Compound II, CompoundIII-d, or Compound III. For example, a candidate composition could betested to determine whether it inhibits the time to onset of solventmediated crystallization, or the percent conversion at a given timeunder controlled conditions, by at least 50%, 75%, or 100% as well asthe reference preparation, or a candidate composition could be tested todetermine if it has improved bioavailability or solubility relative tocrystalline Compound I, Compound II, Compound III-d, or Compound III.

In some embodiments, the first solid dispersion comprises a cellulosepolymer. For example, the first solid dispersion comprises hydroxypropylmethylcellulose (HPMC). In some embodiments, the first solid dispersioncomprises a weight ratio of HPMC to Compound II ranging from 1:10 to1:1. In some instances, the weight ratio of HPMC to Compound II is from1:3 to 1:5.

In some embodiments, the second solid dispersion comprises a cellulosepolymer. For example, the second solid dispersion compriseshydroxypropyl methylcellulose acetate succinate (HPMCAS).

In some embodiments, each of the first and second solid dispersionscomprises a plurality of particles having a mean particle diameter of 5to 100 microns. In some embodiments, the particles have a mean particlediameter of 5 to 30 microns. In some embodiments, the particles have amean particle diameter of 15 microns.

In some embodiments, the first solid dispersion comprises from 70 wt %to 90 wt % (e.g., from 75 wt % to 85 wt %) of Compound II.

In some embodiments, the second solid dispersion comprises from 70 wt %to 90 wt % (e.g., from 75 wt % to 85 wt %) of Compound III-d or III.

In some embodiments, each of the first and second solid dispersions is aspray dried dispersion.

In some embodiments, the pharmaceutical composition disclosed hereinfurther comprise one or more pharmaceutically acceptable excipients,such as pharmaceutically acceptable vehicles, adjuvants, or carriers.

Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, andEncyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C.Boylan, 1988-1999, Marcel Dekker, New York, the contents of each ofwhich is incorporated by reference herein, disclose various carriersused in formulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of thedisclosure, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this disclosure.

In one embodiment, the pharmaceutical composition of the disclosurecomprise one or more fillers, a disintegrant, and a lubricant.

Fillers suitable for the pharmaceutical compositions disclosed hereinare compatible with the other ingredients of the pharmaceuticalcompositions, i.e., they do not substantially reduce the solubility, thehardness, the chemical stability, the physical stability, or thebiological activity of the pharmaceutical compositions. Exemplaryfillers include: celluloses, modified celluloses, (e.g. sodiumcarboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose,hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose,calcium phosphates, dibasic calcium phosphate, starches (e.g. cornstarch, potato starch), sugars (e.g., mannitol, lactose, sucrose, or thelike), or any combination thereof. In one embodiment, the filler ismicrocrystalline cellulose.

In some embodiments, the pharmaceutical compositions comprises one ormore fillers in an amount of at least 5 wt % (e.g., at least 20 wt %, atleast 30 wt %, or at least 40 wt %) by weight of the pharmaceuticalcomposition. For example, the pharmaceutical compositions comprise from10 wt % to 60 wt % (e.g., from 20 wt % to 55 wt %, from 25 wt % to 50 wt%, or from 27 wt % to 45 wt %) of filler, by weight of thepharmaceutical composition. In another example, the pharmaceuticalcomposition s comprise at least 20 wt % (e.g., at least 30 wt % or atleast 40 wt %) of microcrystalline cellulose, for example MCC AvicelPH102 or Avicel PH101, by weight of the pharmaceutical composition. Inyet another example, the pharmaceutical compositions comprise from 10 wt% to 60 wt % (e.g., from 20 wt % to 55 wt % or from 25 wt % to 45 wt %)of microcellulose, by weight of the pharmaceutical composition.

Disintegrants suitable for the pharmaceutical compositions disclosedherein can enhance the dispersal of the pharmaceutical compositions andare compatible with the other ingredients of the pharmaceuticalcompositions, i.e., they do not substantially reduce the chemicalstability, the physical stability, the hardness, or the biologicalactivity of the pharmaceutical compositions. Exemplary disintegrantsinclude croscarmellose sodium, sodium starch glycolate, crospovidone ora combination thereof. In one embodiment, the disintegrant iscroscarmellose sodium.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise disintegrant in an amount of 10 wt % or less (e.g., 7 wt % orless, 6 wt % or less, or 5 wt % or less) by weight of the pharmaceuticalcomposition. For example, the pharmaceutical compositions comprise from1 wt % to 10 wt % (e.g., from 1.5 wt % to 7.5 wt % or from 2.5 wt % to 6wt %) of disintegrant, by weight of the pharmaceutical composition. Inanother example, the pharmaceutical compositions comprise 10 wt % orless (e.g., 7 wt % or less, 6 wt % or less, or 5 wt % or less) ofcroscarmellose sodium, by weight of the pharmaceutical composition. Inyet another example, the pharmaceutical compositions comprise from 1 wt% to 10 wt % (e.g., from 1.5 wt % to 7.5 wt % or from 2.5 wt % to 6 wt%) of croscarmellose sodium, by weight of the pharmaceuticalcomposition. In some examples, the pharmaceutical compositions comprisefrom 0.1% to 10 wt % (e.g., from 0.5 wt % to 7.5 wt % or from 1.5 wt %to 6 wt %) of disintegrant, by weight of the pharmaceutical composition.In still other embodiments, the pharmaceutical compositions comprisefrom 0.5% to 10 wt % (e.g., from 1.5 wt % to 7.5 wt % or from 2.5 wt %to 6 wt %) of disintegrant, by weight of the pharmaceutical composition.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise a lubricant. A lubricant can prevent adhesion of a mixturecomponent to a surface (e.g., a surface of a mixing bowl, a granulationroll, a compression die and/or punch). A lubricant can also reduceinterparticle friction within the granulate and improve the compressionand ejection of compressed pharmaceutical compositions from a granulatorand/or die press. A suitable lubricant for the pharmaceuticalcompositions disclosed herein is compatible with the other ingredientsof the pharmaceutical compositions, i.e., they do not substantiallyreduce the solubility, the hardness, or the biological activity of thepharmaceutical compositions. Exemplary lubricants include magnesiumstearate, sodium stearyl fumarate, calcium stearate, zinc stearate,sodium stearate, stearic acid, aluminum stearate, leucine, glycerylbehenate, hydrogenated vegetable oil or any combination thereof. Inembodiment, the lubricant is magnesium stearate.

In one embodiment, the pharmaceutical compositions comprise a lubricantin an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or3.00 wt % or less, or 2.0 wt % or less) by weight of the pharmaceuticalcomposition. For example, the pharmaceutical compositions comprise from5 wt % to 0.10 wt % (e.g., from 4.5 wt % to 0.5 wt % or from 3 wt % to 1wt %) of lubricant, by weight of the pharmaceutical composition. Inanother example, the pharmaceutical compositions comprise 5 wt % or less(e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0wt % or less) of magnesium stearate, by weight of the pharmaceuticalcomposition. In yet another example, the pharmaceutical compositionscomprise from 5 wt % to 0.10 wt % (e.g., from 4.5 wt % to 0.15 wt % orfrom 3.0 wt % to 0.50 wt %) of magnesium stearate, by weight of thepharmaceutical composition.

In some embodiments, the pharmaceutical compositions disclosed hereinare tablets.

Any suitable spray dried dispersions of Compound II, Compound III-d, andCompound III can be used for the pharmaceutical compositions disclosedherein. Some examples for Compound II and its pharmaceuticallyacceptable salts can be found in WO 2011/119984 and WO 2014/015841, allof which are incorporated herein by reference. Some examples forCompound III and its pharmaceutically acceptable salts can be found inWO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO2013/130669, all of which are incorporated herein by reference.

Pharmaceutical compositions comprising Compound II and Compound III aredisclosed in PCT Publication No. WO 2015/160787, incorporated herein byreference. An exemplary embodiment is shown in the following Table 2:

TABLE 2 Examplary Tablet Comprising 100 mg Compound II and 150 mgCompound III. Amount per Ingredient tablet (mg) Intra-granular CompoundII SDD (spray 125 dried dispersion) (80 wt % Compound II; 20 wt % HPMC)Compound III SDD 187.5 (80 wt % Compound III; 19.5 wt % HPMCAS-HG; 0.5wt % sodium lauryl sulfate) Microcrystalline cellulose 131.4Croscarmellose Sodium 29.6 Total 473.5 Extra-granular Microcrystallinecellulose 112.5 Magnesium Stearate 5.9 Total 118.4 Total uncoated Tablet591.9 Film coat Opadry 17.7 Total coated Tablet 609.6

Pharmaceutical compositions comprising Compound III are disclosed in PCTPublication No. WO 2010/019239, incorporated herein by reference. Anexemplary embodiment is shown in the following Table 3:

TABLE 3 Ingredients for Exemplary Tablet of Compound III. Percent DoseDose Batch Tablet Formulation % Wt./Wt. (mg) (g) Compound III SDD 34.1%187.5 23.9 (80 wt % Compound III; 19.5 wt % HPMCAS-HG; 0.5 wt % sodiumlauryl sulfate) Microcrystalline cellulose 30.5% 167.8 21.4 Lactose30.4% 167.2 21.3 Sodium croscarmellose   3% 16.5 2.1 SLS  0.5% 2.8 0.4Colloidal silicon dioxide  0.5% 2.8 0.4 Magnesium stearate   1% 5.5 0.7Total  100% 550 70

Additional pharmaceutical compositions comprising Compound III aredisclosed in PCT Publication No. WO 2013/130669, incorporated herein byreference. Exemplary mini-tablets (˜2 mm diameter, ˜2 mm thickness, eachmini-tablet weighing 6.9 mg) was formulated to have 50 mg of CompoundIII per 26 mini-tablets and 75 mg of Compound III per 39 mini-tabletsusing the amounts of ingredients recited in Table 4, below.

TABLE 4 Ingredients for mini-tablets for 50 mg and 75 mg potency PercentDose (mg) Tablet Dose Dose (mg) 75 mg Batch Formulation % Wt./Wt. 50 mgpotency potency (g) Compound III SDD 35 62.5 93.8 1753.4 (80 wt %Compound III; 19.5 wt % HPMCAS- HG; 0.5 wt % sodium lauryl sulfate)Mannitol 13.5 24.1 36.2 675.2 Lactose 41 73.2 109.8 2050.2 Sucralose 2.03.6 5.4 100.1 Croscarmellose 6.0 10.7 16.1 300.1 sodium Colloidalsilicon 1.0 1.8 2.7 50.0 dioxide Magnesium stearate 1.5 2.7 4.0 74.2Total 100 178.6 268 5003.2

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % Compound 60 to 65 mg II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt %sodium lauryl sulfate microcrystalline cellulose 75 to 85 mgcroscarmellose sodium (CCS) 25 to 35 mg extragranular: microcrystallinecellulose 115 to 120 mg magnesium stearate 3 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % Compound 60 to 65 mg II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt %sodium lauryl sulfate croscarmellose sodium (CCS) 20 to 25 mgextragranular: microcrystalline cellulose 85 to 95 mg magnesium stearate2 to 6 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 25 to 35 mg microcrystallinecellulose 195 to 200 mg magnesium stearate 3 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 85 to 95 mg magnesium stearate 2 to 6 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 30 mg microcrystallinecellulose 135 to 145 mg magnesium stearate 2 to 6 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 35 to 40 mg lactosemonohydrate 105 to 115 mg microcrystalline cellulose 220 to 230 mgcolloidal silicon dioxide 1 to 5 mg magnesium stearate 4 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 30 mg lactosemonohydrate 40 to 50 mg microcrystalline cellulose 90 to 100 mgcolloidal silicon dioxide 1 to 5 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 30 mg microcrystallinecellulose 135 to 145 mg colloidal silicon dioxide 1 to 5 mg magnesiumstearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound 60 to 65 mg II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII-d, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 30 mg microcrystallinecellulose 135 to 145 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % Compound 60 to 65 mg II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate microcrystalline cellulose 75 to 85 mg croscarmellosesodium (CCS) 25 to 35 mg extragranular: microcrystalline cellulose 115to 120 mg magnesium stearate 3 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 85 to 9 mg extragranular: microcrystalline cellulose 115 to120 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg extragranular:microcrystalline cellulose 85 to 95 mg magnesium stearate 2 to 6 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg extragranular:microcrystalline cellulose 270 to 275 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 85 to 90 mg extragranular: croscarmellose sodium (CCS) 5 to 10mg microcrystalline cellulose 105 to 115 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate microcrystalline cellulose 105 to 115 mg extragranular:croscarmellose sodium (CCS) 25 to 35 mg microcrystalline cellulose 85 to90 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: Compound I 90to 110 mg solid dispersion containing 80 wt % 60 to 65 mg Compound II,20 wt % hypromellose solid dispersion containing 80 wt % Compound 90 to95 mg III, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate microcrystalline cellulose 195 to 200 mg extragranular:croscarmellose sodium (CCS) 25 to 35 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: soliddispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 12 to 17 mg microcrystallinecellulose 60 to 70 mg extragranular: Compound I 90 to 110 mgmicrocrystalline cellulose 95 to 105 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition intragranular: soliddispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 10 to 20 mg microcrystallinecellulose 60 to 70 mg extragranular: Compound I 90 to 110 mgmicrocrystalline cellulose 195 to 205 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 25 to 35 mg microcrystallinecellulose 195 to 205 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 200 to 210 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 85 to 95 mg magnesium stearate 2 to 6 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 20 to 25 mg microcrystallinecellulose 270 to 275 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 25 to 35 mg microcrystallinecellulose 195 to 205 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 25 to 35 mg microcrystallinecellulose 195 to 205 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % 60 to 65 mg Compound II, 20 wt %hypromellose solid dispersion containing 80 wt % Compound 90 to 95 mgIII, 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodiumlauryl sulfate croscarmellose sodium (CCS) 25 to 35 mg microcrystallinecellulose 195 to 200 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound II, 60 to 65 mg 20 wt %hypromellose solid dispersion containing 80 wt % Compound III, 90 to 95mg 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodium laurylsulfate croscarmellose sodium (CCS) 12 to 17 mg microcrystallinecellulose 160 to 170 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

mg per pharmaceutical Component composition Compound I 90 to 110 mgsolid dispersion containing 80 wt % Compound II, 60 to 65 mg 20 wt %hypromellose solid dispersion containing 80 wt % Compound III, 90 to 95mg 19.5 wt % hypromellose acetate succinate, and 0.5 wt % sodium laurylsulfate croscarmellose sodium (CCS) 10 to 20 mg microcrystallinecellulose 260 to 270 mg magnesium stearate 2 to 7 mg

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 12 wt % to 30 wt % Compound(II)  5 wt % to 15 wt % Compound III-d or 10 wt % to 25 wt % Compound(III) Croscarmellose sodium 3 wt %-8 wt % Microcrystalline cellulose 20wt % to 45 wt % Magnesium stearate 0.5 wt % to 2 wt % 

In some embodiments, the pharmaceutical composition disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    18% to 23 wt % Compound (II) 8 wt % to 12 wt % Compound III-d or    13% to 18 wt % Compound (III)Croscarmellose sodium 3 wt %-7 wt % Microcrystalline cellulose 35 wt %to 45 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    15% to 25 wt % Compound (II) 5 wt % to 10 wt % Compound III-d or  7 wt % to 15 wt % Compound (III)Croscarmellose sodium 3 wt %-7 wt % Microcrystalline cellulose 30 wt %to 50 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    20% to 25 wt % Compound (II) 7 wt % to 15wt % Compound III-d or    15% to 20 wt % Compound (III)Croscarmellose sodium 3 wt %-7 wt % Microcrystalline cellulose 15 wt %to 25 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    20% to 25 wt % Compound (II)7 wt % to 15 wt   Compound III-d or    15% to 20 wt % Compound (III)Croscarmellose sodium 3 wt %-7 wt % Microcrystalline cellulose 25 wt %to 35 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    22% to 28 wt % Compound (II)10 wt % to 15 wt % Compound III-d or    15% to 25 wt % Compound (III)Croscarmellose sodium 3 wt %-7 wt % Microcrystalline cellulose 15 wt %to 25 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I)    15% to 20 wt % Compound (II) 7 wt % to 15 wt % Compound III-d or 10 wt % to 15 wt % Compound (III)Croscarmellose sodium 3 wt %-5 wt % Microcrystalline cellulose 45 wt %to 55 wt % Magnesium stearate 0.5 wt % to 1.5 wt %

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 20.5 ± 0.5 Compound (II) 10.2 ±0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 40.5 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 (Intragradular)Compound (II) 10.2 ± 0.5 Compound III-d or 15.4 ± 0.5 Compound (III)Croscarmellose  6.0 ± 0.5 sodium Microcrystalline 16.5 ± 0.5 celluloseEG Microcrystalline 24.0 ± 0.5 (Extragradular) cellulose Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 26.9 ± 0.5 Compound (II) 16.8 ±0.5 Compound III-d or 25.3 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 24.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 26.9 ± 0.5 Compound (II)16.8 ± 0.5 Compound III-d or 25.3 ± 0.5 Compound (III) Croscarmellosesodium  6.0 ± 0.5 EG Microcrystalline 24.0 ± 0.5 cellulose Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 23.4 ± 0.5 Compound (II) 11.7 ±0.5 Compound III-d or 17.6 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 33.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 23.42 ± 0.5  Compound (II)11.7 ± 0.5 Compound III-d or 17.6 ± 0.5 Compound (III) Microcrystalline33.0 ± 0.5 cellulose Croscarmellose  6.0 ± 0.5 sodium EG Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 20.5 ± 0.5 Compound (II) 10.3 ±0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 40.5 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)10.3 ± 0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellosesodium  6.0 ± 0.5 Microcrystalline cellulose 16.5 ± 0.5 EGMicrocrystalline cellulose 24.0 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 20.5 ± 0.5 Compound (II) 12.8 ±0.5 Compound III-d or 19.2 ± 0.5 Compound (III) Croscarmellose sodium 4.5 ± 0.5 Microcrystalline cellulose 40.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)12.8 ± 0.5 Compound III-d or 19.2 ± 0.5 Compound (III) Croscarmellosesodium  4.5 ± 0.5 Microcrystalline cellulose 18.0 ± 0.5 EGMicrocrystalline cellulose 24.0 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 26.9 ± 0.5 Compound (II) 13.5 ±0.5 Compound III-d or 20.2 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 24.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 26.9 ± 0.5 Compound (II)13.5 ± 0.5 Compound III-d or 20.2 ± 0.5 Compound (III) Croscarmellosesodium 6.00 ± 0.5 EG Microcrystalline cellulose 24.0 ± 0.5 Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 18.0 ± 0.5 Compound (II)  9.0 ±0.5 Compound III-d or 13.5 ± 0.5 Compound (III) Croscarmellose sodium 4.0 ± 0.5 Microcrystalline cellulose 49.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 18.0 ± 0.5 Compound (II) 9.0 ± 0.5 Compound III-d or 13.5 ± 0.5 Compound (III) Croscarmellosesodium  4.0 ± 0.5 EG Microcrystalline cellulose 49.0 ± 0.5 Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 20.5 ± 0.5 Compound (II) 10.3 ±0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 40.5 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)10.3 ± 0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellosesodium  4.5 ± 0.5 Microcrystalline cellulose 18.0 ± 0.5 EGCroscarmellose sodium  1.5 ± 0.5 Microcrystalline cellulose 22.5 ± 0.5Magnesium stearate 1.00 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)12.8 ± 0.5 Compound III-d or 19.2 ± 0.5 Compound (III) Microcrystallinecellulose 22.5 ± 0.5 EG Croscarmellose sodium  6.0 ± 0.5Microcrystalline cellulose 18.0 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)10.3 ± 0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Croscarmellosesodium  4.5 ± 0.5 Microcrystalline cellulose  18 ± 0.5 EG Croscarmellosesodium  1.5 ± 0.5 Microcrystalline cellulose 22.5 ± 0.5 Magnesiumstearate   1 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total Component weight of the tablet)IG Compound (I) 20.5 ± 0.5 Compound (II) 10.3 ± 0.5 Compound III-d or15.4 ± 0.5 Compound (III) Croscarmellose sodium  4.5 ± 0.5Microcrystalline cellulose 18.0 ± 0.5 EG Croscarmellose sodium  1.5 ±0.5 Microcrystalline cellulose 22.5 ± 0.5 Magnesium stearate 1.00 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (I) 20.5 ± 0.5 Compound (II)10.2 ± 0.5 Compound III-d or 15.4 ± 0.5 Compound (III) Microcrystallinecellulose 40.5 ± 0.5 EG Croscarmellose sodium  6.0 ± 0.5 Magnesiumstearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 22.7 ± 0.5 Compound (II) 11.3 ±0.5 Compound III-d or 17.0 ± 0.5 Compound (III) Croscarmellose sodium 3.4 ± 0.5 Microcrystalline cellulose 37.6 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (II) 11.3 ± 0.5 Compound III-dor Compound 17.0 ± 0.5 (III) Croscarmellose sodium  3.4 ± 0.5Microcrystalline cellulose 14.9 ± 0.5 EG Compound (I) 22.7 ± 0.5Microcrystalline cellulose 22.7 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 18.4 ± 0.5 Compound (II)  9.2 ±0.5 Compound III-d or Compound (III) 13.8 ± 0.5 Croscarmellose sodium 2.7 ± 0.5 Microcrystalline cellulose 49.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) IG Compound (II)  9.2 ± 0.5 Compound III-dor Compound 13.8 ± 0.5 (III) Croscarmellose sodium  2.7 ± 0.5Microcrystalline cellulose 12.1 ± 0.5 EG Compound (I) 18.4 ± 0.5Microcrystalline cellulose 36.9 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 15.6 ± 0.5 Compound (II)  9.8 ±0.5 Compound III-d or Compound (III) 14.6 ± 0.5 Croscarmellose sodium 6.0 ± 0.5 Lactose monohydrate 17.5 ± 0.5 Microcrystalline cellulose35.0 ± 0.5 Colloidal silicon dioxide  0.5 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 23.4 ± 0.5 Compound (II) 11.7 ±0.5 Compound III-d or Compound (III) 17.6 ± 0.5 Croscarmellose sodium 6.0 ± 0.5 Lactose monohydrate 10.8 ± 0.5 Microcrystalline cellulose21.7 ± 0.5 Colloidal silicon dioxide  0.5 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 23.4 ± 0.5 Compound (II) 11.7 ±0.5 Compound III-d or Compound (III) 17.6 ± 0.5 Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 32.5 ± 0.5 Colloidal silicondioxide  0.5 ± 0.5 Magnesium stearate  1.0 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Composition (% w/w) (based on the total weight of the Componentpharmaceutical composition) Compound (I) 23.4 ± 0.5 Compound (II) 11.7 ±0.5 Compound III-d or Compound (III) 17.6 ± 0.5 Croscarmellose sodium 6.0 ± 0.5 Microcrystalline cellulose 33.0 ± 0.5 Magnesium stearate  1.0± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

-   -   (A) an intragranular portion that comprises:    -   (a) 10 mg to 110 mg of Compound I;    -   (b) 25 mg to 70 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion; and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion; and    -   (c) 85 mg to 195 mg, of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 10 mg to 45 mg of croscarmellose sodium; and    -   (e) 40 mg to 115 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 55 mg to 165 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 95 mg to 105 mg of Compound I;    -   (b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 185 mg to 190 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 35 mg to 45 mg of croscarmellose sodium;    -   (e) 105 mg to 115 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 155 mg to 165 mg of said microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 45 mg to 55 mg of Compound I;    -   (b) 25 mg to 55 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 90 mg to 100 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 15 mg to 25 mg of croscarmellose sodium;    -   (e) 50 mg to 60 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 75 mg to 85 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 45 mg to 55 mg of Compound I;    -   (b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 185 mg to 190 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 30 mg to 40 mg of croscarmellose sodium;    -   (e) 90 mg to 100 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 130 mg to 145 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 20 mg to 30 mg of Compound I;    -   (b) 30 mg to 35 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 90 mg to 100 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 15 mg to 25 mg of croscarmellose sodium;    -   (e) 45 mg to 50 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 65 mg to 70 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 20 mg to 30 mg of Compound I;    -   (b) 60 mg to 65 mg of of a first solid dispersion comprising 80        wt % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 185 mg to 190 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 35 mg to 45 mg of croscarmellose sodium;    -   (e) 80 mg to 90 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 120 mg to 130 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

(A) an intragranular portion that comprises:

-   -   (a) 10 mg to 15 mg of Compound I;    -   (b) 25 mg to 35 mg of a first solid dispersion comprising 80 wt        % Compound II relative to the total weight of the first solid        dispersion and 20 wt % of a hydroxypropyl methylcellulose        relative to the total weight of the first solid dispersion;    -   (c) 90 mg to 100 mg of a second solid dispersion comprising 80        wt % of Compound III relative to the total weight of the second        solid dispersion; 0.5 wt % of sodium lauryl sulfate relative to        the total weight of the second solid dispersion; and 19.5 wt %        of a hydroxypropyl methylcellulose acetate succinate to the        total weight of the second solid dispersion;    -   (d) 10 mg to 20 mg of croscarmellose sodium;    -   (e) 40 mg to 50 mg of microcrystalline cellulose; and        (B) an extragranular portion that comprises:    -   (f) 60 mg to 65 mg of microcrystalline cellulose; and    -   (g) 2 mg to 7 mg of magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Material Name mg per tablet Intra Granular Compound I 100.0 ± 0.5 Compound II SDD (80 wt % 62.5 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 93.8 ± 0.5 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 29.3 ± 0.5Microcrystalline cellulose 80.5 ± 0.5 Extra Granular Microcrystallinecellulose 117.1 ± 0.5  Magnesium stearate  4.9 ± 0.5 Coating 14.6 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Ingredient Amount per tablet (mg) Intra-granular Compound I 100.0 ± 0.5Compound II SDD (80 wt %  62.5 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.6 ± 0.5 Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium  29.3 ± 0.5Microcrystalline cellulose  80.5 ± 0.5 Extra-granular Microcrystallinecellulose 117.1 ± 0.5 Magnesium Stearate  4.9 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Ingredient Amount per tablet (mg) Intra-granular Compound I 100.0 ± 0.5 Compound II SDD (80 wt % 62.4 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.6 ± 0.5  Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium 22.3 ± 0.5Extra-granular Microcrystalline cellulose 89.1 ± 0.5 Magnesium Stearate 3.7 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Ingredient Amount per tablet (mg) Compound I  100 ± 0.5 Compound II SDD(80 wt % Compound II and 20 wt %  62.5 ± 0.5 HPMC) Compound III SDD (80wt % Compound III, 19.5 wt % 187.6 ± 0.5 HPMCAS, and 0.5 wt % sodiumlauryl sulfate) Microcrystalline cellulose 140.9 ± 0.5 CroscarmelloseSodium  25.6 ± 0.5 Magnesium stearate  4.3 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per tablet Ingredient (mg) Intra- Compound I 100 ± 0.5 granularCompound II SDD (80 wt % 62.5 ± 0.5  Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.5 ± 0.5  Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium  40 ± 0.5Microcrystalline cellulose 110 ± 0.5 Extra- Microcrystalline cellulose160 ± 0.5 granular Magnesium stearate  6.7 ± 0.5 Film coat  20 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per Ingredient tablet (mg) Intra- Compound I 50 ± 0.5 granularCompound II SDD (80 wt % 31.2 ± 0.5  Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 93.7 ± 0.5  Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 20 ± 0.5Microcrystalline cellulose 55 ± 0.5 Extra- Microcrystalline cellulose 80± 0.5 granular Magnesium stearate 3.3 ± 0.5  Film coat 10 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per Ingredient tablet (mg) Intra-granular Compound I  50 ± 0.5Compound II SDD (80 wt % 62.5 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.5 ± 0.5  Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 34.3 ± 0.5Microcrystalline cellulose 94.3 ± 0.5 Extra-granular Microcrystallinecellulose 137.1 ± 0.5  Magnesium stearate  5.7 ± 0.5 Film coat 17.1 ±0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per Ingredient tablet (mg) Intra-granular Compound I  25 ± 0.5Compound II SDD (80 wt % 31.2 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 93.7 ± 0.5 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 17.1 ± 0.5Microcrystalline cellulose 47.1 ± 0.5 Extra-granular Microcrystallinecellulose 68.6 ± 0.5 Magnesium stearate  2.9 ± 0.5 Film coat  8.6 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per Ingredient tablet (mg) Intra-granular Compound I  25 ± 0.5Compound II SDD (80 wt % 62.5 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.5 ± 0.5  Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 31.4 ± 0.5Microcrystalline cellulose 86.4 ± 0.5 Extra-granular Microcrystallinecellulose 125.7 ± 0.5  Magnesium stearate  5.2 ± 0.5 Film coat 15.7 ±0.5

In some embodiments, the pharmaceutical compositions disclosed hereincomprise:

Amount per Ingredient tablet (mg) Intra-granular Compound I 12.5 ± 0.5Compound II SDD (80 wt % 31.2 ± 0.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 93.7 ± 0.5 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 15.7 ± 0.5Microcrystalline cellulose 43.2 ± 0.5 Extra-granular Microcrystallinecellulose 62.9 ± 0.5 Magnesium stearate  2.6 ± 0.5 Film coat  7.9 ± 0.5

In some embodiments, the pharmaceutical compositions disclosed hereinare tablets.

Processes of Making Tablets

The tablets of the disclosure can be produced by compacting orcompressing an admixture or composition, for example, powder orgranules, under pressure to form a stable three-dimensional shape (e.g.,a tablet). As used herein, “tablet” includes compressed pharmaceuticaldosage unit forms of all shapes and sizes, whether coated or uncoated.In some embodiments, the methods of preparing the tablets disclosedherein comprise (a) mixing Compound I and the first and second soliddispersions to form a first mixture; and (b) compressing a tabletmixture comprising the first mixture into a tablet. As used herein, theterm “mixing” include mixing, blending and combinding. In someembodiments, the tablet mixture further comprises one or morepharmaceutically acceptable excipients, and the methods further comprisemixing the first mixture with said one or more excipients to form thetablet mixture. Mixing the first mixture with one or more excipients canbe performed in one or more steps. In one embodiment, the one or moreexcipients are mixed to form a second mixture; and the first and secondmixtures are mixed together to form the tablet mixture prior to thecompression step. In one embodiment, the one or more excipients can bemixed with the first mixture in more than one parts, for example, someexcipients mixed with the first mixture first and the other excipientsfollowed later. In some embodiments, the tablets disclosed herein anintra-granular part and an extra-grandular part as described above, andone or more excipients included in the intra-granular part are mixed toform a second mixture, and one or more excipients included in theextra-granular part are mixed to form a third mixture, and the firstmixture are combined with the second mixture, and the combined first andsecond mixtures are combined with the third mixture to form a tabletmixture.

In some embodiments, the methods of preparing the tablets disclosedherein comprise: (a) mixing Compound I and the first and second soliddispersions to form a first mixture; (b) mixing the first mixture withone or more of microcrystalline cellulose, croscarmellose sodium andmagnesium stearate to form a tablet mixture; and (c) compressing thetablet mixture into a tablet.

In some embodiments, the methods of preparing the tablets disclosedherein comprise:

(a) mixing Compound I and the first and second solid dispersionsdescribed above to form a first mixture; (b) mixing one or more ofmicrocrystalline cellulose, croscarmellose sodium and magnesium stearatein an intra-granular part to form a second mixture; (c) mixing one ormore of microcrystalline cellulose, croscarmellose sodium, and magnesiumstearate in an extra-granular part to form a third mixture; (d) mixingthe first, second, and third mixtures to form a tablet mixture; and (e)compressing the tablet mixture comprising the first, second and thirdmixtures into a tablet. It is noted that steps (a), (b), and (c) mayoccur in any order.

In some embodiments, the methods disclosed herein further comprisecoating the tablet.

In some embodiments, the methods disclosed herein further comprisegranulating the first, second, and/or third mixtures prior to thecompression the tablet mixture. Any suitable methods known in the artfor granulation and compression of pharmaceutical compositions can beused. It is noted that step (a) can occur prior to step (b) or step (b)can occur prior to step (a).

Granulation and Compression

In some embodiments, solid forms, including powders comprising one ormore APIs (e.g., Compound I, Compound II, Compound III-d and/or CompoundIII) and the included pharmaceutically acceptable excipients (e.g.filler, diluent, disintegrant, surfactant, glidant, binder, lubricant,or any combination thereof) can be subjected to a dry granulationprocess. The dry granulation process causes the powder to agglomerateinto larger particles having a size suitable for further processing. Drygranulation can improve the flowability of a mixture to produce tabletsthat comply with the demand of mass variation or content uniformity.

In some embodiments, formulations can be produced using one or moremixing and dry granulations steps. The order and the number of themixing by granulation. At least one of the excipients and the API(s) canbe subject to dry granulation or wet high shear granulation or twinscrew wet granulation before compression into tablets. Dry granulationcan be carried out by a mechanical process, which transfers energy tothe mixture without any use of any liquid substances (neither in theform of aqueous solutions, solutions based on organic solutes, ormixtures thereof) in contrast to wet granulation processes, alsocontemplated herein. Generally, the mechanical process requirescompaction such as the one provided by roller compaction. An example ofan alternative method for dry granulation is slugging. In someembodiments, wet granulations instead of the dry granulation can beused.

In some embodiments, roller compaction is a granulation processcomprising mechanical compacting of one or more substances. In someembodiments, a pharmaceutical composition comprising an admixture ofpowders is pressed, that is roller compacted, between two rotatingrollers to make a solid sheet that is subsequently crushed in a sieve toform a particulate matter. In this particulate matter, a closemechanical contact between the ingredients can be obtained. An exampleof roller compaction equipment is Minipactor® a Gerteis 3W-Polygran fromGerteis Maschinen+Processengineering AG.

In some embodiments, tablet compression according to the disclosure canoccur without any use of any liquid substances (neither in the form ofaqueous solutions, solutions based on organic solutes, or mixturesthereof), i.e., a dry granulation process. In a typical embodiment theresulting core or tablet has a tensile strength in the range of from 0.5MPa to 3.0 MPa; such as 1.0 to 2.5 MPa, such as in the range of 1.5 to2.0 MPa.

In some embodiments, the ingredients are weighed according to theformula set herein. Next, all of the intragranular ingredients aresifted and mixed well. The ingredients can be lubricated with a suitablelubricant, for example, magnesium stearate. The next step can comprisecompaction/slugging of the powder admixture and sized ingredients. Next,the compacted or slugged blends are milled into granules and mayoptionally be sifted to obtain the desired size. Next, the granules canbe further blended or lubricated with, for example, magnesium stearate.Next, the granular composition of the disclosure can be compressed onsuitable punches into various pharmaceutical formulations in accordancewith the disclosure. Optionally the tablets can be coated with a filmcoat.

Another aspect of the disclosure provides a method for producing apharmaceutical composition comprising an admixture of a compositioncomprising one or more APIs (e.g., Compound I, Compound II, CompoundIII-d and/or Compound III); and one or more excipients selected from:one or more fillers, a diluent, a binder, a glidant, a surfactant, alubricant, a disintegrant, and compressing the composition into atablet.

Coating

In some embodiments, the tablets disclosed herein can be coated with afilm coating and optionally labeled with a logo, other image and/or textusing a suitable ink. In still other embodiments, the tablets disclosedherein can be coated with a film coating, waxed, and optionally labeledwith a logo, other image and/or text using a suitable ink. Suitable filmcoatings and inks are compatible with the other ingredients of thetablets, e.g., they do not substantially reduce the solubility, thechemical stability, the physical stability, the hardness, or thebiological activity of the tablets. The suitable colorants and inks canbe any color and are water based or solvent based. In one embodiment,the tablets disclosed herein are coated with a colorant and then labeledwith a logo, other image, and/or text using a suitable ink.

In some embodiments, the tablets disclosed herein are coated with a filmthat comprises 2-6 wt % by the weight of the uncoated tablet. In someembodiments, the film comprises one or more colorants and/or pigments.In some embodiments, the tablets disclosed herein are coated with a filmthat comprises one or more colorants and/or pigments and wherein thefilm comprises 2-5 wt % by the weight of the uncoated tablet. In someembodiments, the tablets disclosed herein are coated with a film thatcomprises one or more colorants and/or pigments and wherein the filmcomprises 2-4 wt % by the weight of the uncoated tablet. The coloredtablets can be labeled with a logo and text indicating the strength ofthe active ingredient in the tablet using a suitable ink.

Methods of Treatment

The tablets disclosed herein can be administered once a day, twice aday, or three times a day. In some embodiments, one or more of thetablets are administered per dosing. In some embodiments, two tabletsper dosing are administered. In some embodiments, two tablets per dosingare administered once a day. In some embodiments, two tablets per dosingare administered twice a day. An effective amount of the APIs (e.g.,Compound (I)) is administered to the patient with or using one or moretablets disclosed herein.

The tablets disclosed herein are useful for treating cystic fibrosis.

In some aspects, the tablets disclosed herein can be employed incombination therapies. In some embodiments, the tablets disclosed hereincan be administered concurrently with, prior to, or subsequent to, atleast one active pharmaceutical ingredients or medical procedures.

In some embodiments, the pharmaceutical compositions are a tablet. Insome embodiments, the tablets are suitable for oral administration.

The tablets disclosed herein, optionally with additional activepharmaceutical ingredients or medical procedures are useful for treatingcystic fibrosis in a patient.

Compounds I, II, III-d, and III are as depicted above. Compound IV isdepicted as having the following structure:

A chemical name for Compound IV is3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid.

A CFTR mutation may affect the CFTR quantity, i.e., the number of CFTRchannels at the cell surface, or it may impact CFTR function, i.e., thefunctional ability of each channel to open and transport ions. Mutationsaffecting CFTR quantity include mutations that cause defective synthesis(Class I defect), mutations that cause defective processing andtrafficking (Class II defect), mutations that cause reduced synthesis ofCFTR (Class V defect), and mutations that reduce the surface stabilityof CFTR (Class VI defect). Mutations that affect CFTR function includemutations that cause defective gating (Class III defect) and mutationsthat cause defective conductance (Class IV defect). Some CFTR mutationsexhibit characteristics of multiple classes.

In some embodiments, disclosed herein methods of treating, lessening theseverity of, or symptomatically treating cystic fibrosis in a patientcomprising administering an effective amount of a compound,pharmaceutically acceptable salt thereof, or a deuterated analog of anyof the foregoing; or a pharmaceutical composition, of this disclosure toa patient, such as a human, wherein said patient has cystic fibrosis. Insome embodiments, the patient has an F508del/minimal function (MF)genotype, F508del/F508del genotype (homozygous for the F508delmutation), F508del/gating genotype, or F508del/residual function (RF)genotype. In some embodiments the patient is heterozygous and has oneF508del mutation.

As used herein, “minimal function (MF) mutations” refer to CFTR genemutations associated with minimal CFTR function (little-to-nofunctioning CFTR protein) and include, for example, mutations associatedwith severe defects in ability of the CFTR channel to open and close,known as defective channel gating or “gating mutations”; mutationsassociated with severe defects in the cellular processing of CFTR andits delivery to the cell surface; mutations associated with no (orminimal) CFTR synthesis; and mutations associated with severe defects inchannel conductance. Table C below includes a non-exclusive list of CFTRminimal function mutations, which are detectable by an FDA-clearedgenotyping assay. In some embodiments, a mutation is considered a MFmutation if it meets at least 1 of the following 2 criteria:

-   -   (1) biological plausibility of no translated protein (genetic        sequence predicts the complete absence of CFTR protein), or    -   (2) in vitro testing that supports lack of responsiveness to        Compound II, Compound III or the combination of Compound II and        Compound III, and evidence of clinical severity on a population        basis (as reported in large patient registries).

In some embodiments, the minimal function mutations are those thatresult in little-to-no functioning CFTR protein and are not responsivein vitro to Compound II, Compound III, or the combination of Compound IIand Compound III.

In some embodiments, the minimal function mutations are those that arenot responsive in vitro to Compound II, Compound III, or the combinationof Compound II and Compound III. In some embodiments, the minimalfunction mutations are mutations based on in vitro testing met thefollowing criteria in in vitro experiments:

-   -   baseline chloride transport that was <10% of wildtype CFTR, and    -   an increase in chloride transport of <10% over baseline        following the addition of TEZ, IVA, or TEZ/IVA in the assay.

In some embodiments, patients with at least one minimal functionmutation exhibit evidence of clinical severity as defined as:

-   -   average sweat chloride >86 mmol/L, and    -   prevalence of pancreatic insufficiency (PI) >50%.

Patients with an F508del/minimal function genotype are defined aspatients that are heterozygous F508del-CFTR with a second CFTR allelecontaining a minimal function mutation. In some embodiments, patientswith an F508del/minimal function genotype are patients that areheterozygous F508del-CFTR with a second CFTR allele containing amutation that results in a CFTR protein with minimal CFTR function(little-to-no functioning CFTR protein) and that is not responsive invitro to Compound II, Compound III, or the combination of Compound IIand Compound III.

In some embodiments, minimal function mutations can be determined using3 major sources:

-   -   biological plausibility for the mutation to respond (i.e.,        mutation class)    -   evidence of clinical severity on a population basis (per CFTR2        patient registry; accessed on 15 Feb. 2016)        -   average sweat chloride >86 mmol/L, and        -   prevalence of pancreatic insufficiency (PI) >50%    -   in vitro testing        -   utations resulting in baseline chloride transport <10% of            wild-type CFTR were considered minimal function        -   utations resulting in chloride transport <10% of wild-type            CFTR following the addition of Compound II and/or Compound            III were considered nonresponsive.

As used herein, a “residual function mutations” refer to are Class IIthrough V mutations that have some residual chloride transport andresult in a less severe clinical phenotype. Residual function mutationsare mutation in the CFTR gene that result in reduced protein quantity orfunction at the cell surface which can produce partial CFTR activity.

Non-limiting examples of CFTR gene mutations known to result in aresidual function phenotype include a CFTR residual function mutationselected from 2789+5G→A, 3849+1 OkbC→T, 3272-26A→G, 711+3A→G, E56K,P67L, R74W, DllOE, DllOH, R117C, L206W, R347H, R352Q, A455E, D579G,E831X, S945L, S977F, F1052V, R1070W, F1074L, Dl 152H, D1270N, El93K, andKl060T. For example, CFTR mutations that cause defective mRNA splicing,such as 2789+507 A, result in reduced protein synthesis, but deliversome functional CFTR to the surface of the cell to provide residualfunction. Other CFTR mutations that reduce conductance and/or gating,such as Rl 17H, result in a normal quantity of CFTR channels at thesurface of the cell, but the functional level is low, resulting inresidual function. In some embodiments, the CFTR residual functionmutation is selected from R117H, S1235R, I1027T, R668C, G576A, M470V,L997F, R75Q, R1070Q, R31C, D614G, G1069R, R1162L, E56K, A1067T, E193K,and K1060T. In some embodiments, the CFTR residual function mutation isselected from R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q,R1070Q, R31C, D614G, G1069R, R1162L, E56K, and A1067T.

Residual CFTR function can be characterized at the cellular (in vitro)level using cell based assays, such as an FRT assay (Van Goar, F. et al.(2009) PNAS Vol. 106, No. 44, 18825-18830; and Van Goor, F. et al.(2011) PNAS Vol. 108, No. 46, 18843-18846), to measure the amount ofchloride transport through the mutated CFTR channels. Residual functionmutations result in a reduction but not complete elimination of CFTRdependent ion transport. In some embodiments, residual functionmutations result in at least about 10% reduction of CFTR activity in anFRT assay. In some embodiments, the residual function mutations resultin up to about 90% reduction in CFTR activity in an FRT assay.

Patients with an F508del/residual function genotype are defined aspatients that are heterozygous F508del-CFTR with a second CFTR allelethat contains a mutation that results in reduced protein quantity orfunction at the cell surface which can produce partial CFTR activity.

Patients with an F508del/gating mutation genotype are defined aspatients that are heterozygous F508del-CFTR with a second CFTR allelethat contains a mutation associated with a gating defect and clinicallydemonstrated to be responsive to Compound III. Examples of suchmutations include: G178R, S549N, S549R, G551D, G551S, G1244E, S1251N,S1255P, and G1349D.

In some embodiments, the methods of treating, lessening the severity of,or symptomatically treating cystic fibrosis disclosed herein are eachindependently produces an increase in chloride transport above thebaseline chloride transport of the patient.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient is heterozygous for F508del, and the other CFTR genetic mutationis any CF-causing mutation. In some embodiments, the patient isheterozygous for F508del, and the other CFTR genetic mutation is anyCF-causing mutation, and is expected to be and/or is responsive to anyof the novel compounds disclosed herein, such as Compound I, CompoundII, Compound III and/or Compound IV genotypes based on in vitro and/orclinical data. In some embodiments, the patient is heterozygous forF508del, and the other CFTR genetic mutation is any CF-causing mutation,and is expected to be and/or is responsive to any combinations of (i)the novel compounds disclosed herein, such as Compound I, and (ii)Compound II, and/or Compound III and/or Compound IV genotypes based onin vitro and/or clinical data.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from any of themutations listed in Table A.

TABLE A CF Mutations 078delT 1078delT 11234V 1154insTC 1161delC 1213delT1248 + 1G→A 1249 − 1G→A 124del23bp 1259insA 1288insTA 1341 + 1G−>A 1342− 2A−>C 1461ins4 1471delA 1497delGG 1507del 1525 − 1G→A 1525 − 2A→G1548delG 1577delTA 1609del CA 1677delTA 1716G/A 1717 − 1G→A 1717 − 8G→A1782delA 1811 + 1.6kbA−>G 1811 + 1G−>C 1811 + 1.6kbA→G 1811 + 1G→C 1812− 1G−>A 1898 + 1G−>A 1812 − 1G→A 1824delA 182delT 1119delA 185 + 1G→T1898 + 1G−>T 1898 + 1G→A 1898 + 1G→C 1898 + 3A−>G 1898 + 5G−>T 1924del71949del84 2043delG 2055del9→A 2105-2117del13insAGAAA 2118del14 2143delT2183AA−>G+ 2183AA→G 2183AA→G^(a) 2183delAA−>G# 2183delAA→G 2184delA2184insA 2307insA 2347delG 2556insAT 2585delT 2594delGT 2622 + 1G−>A2622 + IG−>A 2659delC 2711delT 271delT 2721del11 2732insA 2789 + 2insA2789 + 5G→A 2790 − 1G→C 2790 − IG−>C 2869insG 2896insAG 2942insT2957delT 296 + 1G→A 2991del32 3007delG 3028delA 3040G→C 306insA 306insA1138insG 3120G→A 3121 − 1G→A 3121 − 2A→G 3121 − 977_3499 + 248 del25153132delTG 3141del9 3171delC 3195del6 3199del6 3272 − 26A−>G 3500 − 2A→G3600 + 2insT 365-366insT 3659delC 3667ins4 3737delA 3791delC 3821delT3849 + 10kbC→T 3849 + IOkbC−>T 3850 − 1G→A 3850 − 3T−>G 3850 − IG−>A3876delA 3878delG 3905InsT 3905insT 394delTT 4005 + 1G−>A 4005 + 2T−>C4005 + 1G→A 4005 + IG−>A 4010del4 4015delA 4016insT 4021dupT 4040delA405 + 1G→A 405 + 3A→C 405 + IG−>A 406 − 1G→A 406 − IG−>A 4209TGTT−>A4209TGTT→AA 4279insA 4326delTC 4374 + 1G→T 4374 + IG−>T 4382delA4428insGA 442delA 457TAT→G 541delC 574delA 5T 621 + 1G→T 621 + 3A−>G663delT 663delT 1548delG 675del4 711 + 1G−>T 711 + 3A−>G 711 + 1G→T711 + 3A→G 711 + 5G→A 712 − 1G−>T 7T 852del22 935delA 991del5 A1006EA120T A234D A349V A455E A613T A46D A46Db A559T A559Tb A561E C276X C524RC524X CFTRdel2,3 CFTRdele22-23 D110E D110H D1152H D1270N D192G D443YD513G D579G D614G D836Y D924N D979V E1104X E116K E1371X E193K E193XE403D E474K E56K E585X E588V E60K E822K E822X E831X E92K E92X F1016SF1052V F1074L F1099L F191V F311del F311L F508C F508del F575Y G1061RG1069R G1244E G1249R G126D G1349D G149R G178R G194R G194V G27R G27XG314E G330X G458V G463V G480C G542X G550X G551D G551S G576A G622D G628RG628R(G−>A) G970D G673X G85E G91R G970R G970R H1054D H1085P H1085RH1375P H139R H199R H199Y H609R H939R I1005R I1027T I1234V I1269N I1366NI148T I175V I3336K I502T I506S I506T I507del I507del I601F I618T I807MI980K IVS14b + 5G−>A K710X K710X K710X L102R L1065P L1077P L1077PbL1254X L1324P L1335P L138ins L1480P L15P L165S L206W L218X L227R L320VL346P L453S L467P L467Pb L558S L571S L732X L927P L967S L997F M1101KM1101R M152V M1T M1V M265R M470V M952I M952T N1303K P205S P574H P5L P67LP750L P99L Q1100P Q1291H Q1291R Q1313X Q1382X Q1411X Q1412X Q220X Q237EQ237H Q452P Q290X Q359K/T360K Q39X Q414 Q414X E585X Q493X Q525X Q552XQ685X Q890X Q890X Q98R Q98X R1066C R1066H R1066M R1070Q R1070W R1102XR1158X R1162L R1162X R117C R117G R117H R117L R117P R1283M R1283S R170HR258G R31C R31L R334L R334Q R334W R347H R347L R347P R352Q R352W R516GR553Q R553X R560K R560S R560T R668C R709X R74W R751L R75Q R75X R764XR792G R792X R851X R933G S1118F S1159F S1159P S1196X S1235R S1251N S1255PS1255X S13F S341P S434X S466X S489X S492F S4X S549N S549R S549R(A−>C)S549R(T−>G) S589N S737F S912L S912X S945L S977F T1036N T1053I T1246IT338I T604I V1153E V1240G V1293G V201M V232D V456A V456F V520F V562IV754M W1089X W1098C W1098R W1098X W1204X W1282R W1282X W361R W401X W496XW57G W57R W57X W846X Y1014C Y1032C Y1092X Y109N Y122X Y161D Y161S Y563DY563N Y569C Y569D Y569Db Y849X Y913C Y913X

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from G178R, G551S,G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V,G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A,621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A,406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A,1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A,3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G,711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A,1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T,4005+2T->C, 621+3A->G, 1949del84, 3141del9, 3195del6, 3199del6,3905InsT, 4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G,D443Y, D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K,E822K, F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R,G1249R, G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C,G622D, G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P,H139R, H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V,I502T, I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P,L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R,M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P,Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L,R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W,R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F,S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I,T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I,W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D,Y161S, Y563D, Y563N, Y569C, and Y913C.

In some embodiments, the patient has at least one combination mutationchosen from: G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L,L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N,D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A,712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A,2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A,1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C,405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A,1898+1G->T, 4005+2T->C, and 621+3A->G.

In some embodiments, the patient has at least one combination mutationchosen from: 1949del84, 3141del9, 3195del6, 3199del6, 3905InsT,4209TGTT->A, A1006E, A120T, A234D, A349V, A613T, C524R, D192G, D443Y,D513G, D836Y, D924N, D979V, E116K, E403D, E474K, E588V, E60K, E822K,F1016S, F1099L, F191V, F311del, F311L, F508C, F575Y, G1061R, G1249R,G126D, G149R, G194R, G194V, G27R, G314E, G458V, G463V, G480C, G622D,G628R, G628R(G->A), G91R, G970D, H1054D, H1085P, H1085R, H1375P, H139R,H199R, H609R, H939R, I1005R, I1234V, I1269N, I1366N, I175V, I502T,I506S, I506T, I601F, I618T, I807M, I980K, L102R, L1324P, L1335P,L138ins, L1480P, L15P, L165S, L320V, L346P, L453S, L571S, L967S, M1101R,M152V, M1T, M1V, M265R, M952I, M952T, P574H, P5L, P750L, P99L, Q1100P,Q1291H, Q1291R, Q237E, Q237H, Q452P, Q98R, R1066C, R1066H, R117G, R117L,R117P, R1283M, R1283S, R170H, R258G, R31L, R334L, R334Q, R347L, R352W,R516G, R553Q, R751L, R792G, R933G, S1118F, S1159F, S1159P, S13F,S549R(A->C), S549R(T->G), S589N, S737F, S912L, T1036N, T1053I, T1246I,T604I, V1153E, V1240G, V1293G, V201M, V232D, V456A, V456F, V562I,W1098C, W1098R, W1282R, W361R, W57G, W57R, Y1014C, Y1032C, Y109N, Y161D,Y161S, Y563D, Y563N, Y569C, and Y913C.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation G551D. In some embodiments,the patient is homozygous for the G551D genetic mutation. In someembodiments, the patient is heterozygous for the G551D genetic mutation.In some embodiments, the patient is heterozygous for the G551D geneticmutation, having the G551D mutation on one allele and any otherCF-causing mutation on the other allele. In some embodiments, thepatient is heterozygous for the G551D genetic mutation on one allele andthe other CF-causing genetic mutation on the other allele is any one ofF508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T,2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A,3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In someembodiments, the patient is heterozygous for the G551D genetic mutation,and the other CFTR genetic mutation is F508del. In some embodiments, thepatient is heterozygous for the G551D genetic mutation, and the otherCFTR genetic mutation is R117H.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation F508del. In some embodiments,the patient is homozygous for the F508del genetic mutation. In someembodiments, the patient is heterozygous for the F508del geneticmutation wherein the patient has the F508del genetic mutation on oneallele and any CF-causing genetic mutation on the other allele. In someembodiments, the patient is heterozygous for F508del, and the other CFTRgenetic mutation is any CF-causing mutation, including, but not limitedto G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T,2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ΔI507, 1898+1G->A,3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T. In someembodiments, the patient is heterozygous for F508del, and the other CFTRgenetic mutation is G551D. In some embodiments, the patient isheterozygous for F508del, and the other CFTR genetic mutation is R117H.

In some embodiments, the patient has at least one combination mutationchosen from:

D443Y; G576A; R668C, F508C; S1251N, G576A; R668C, G970R; M470V, R74W;D1270N, R74W; V201M, and R74W; V201M; D1270N.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from G178R, G551S,G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V andG1069R. In some embodiments, the patient possesses a CFTR geneticmutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D,S549N, S549R and S1251N. In some embodiments, the patient possesses aCFTR genetic mutation selected from E193K, F1052V and G1069R. In someembodiments, the method produces an increase in chloride transportrelative to baseline chloride transport of the patient of the patient.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from R117C, D110H,R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W,F1074L, D110E, D1270N and D1152H.

In some embodiments, the patient possesses a CFTR genetic mutationselected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A,712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A,2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A,1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C,405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A,1898+1G->T, 4005+2T->C and 621+3A->G. In some embodiments, the patientpossesses a CFTR genetic mutation selected from 1717-1G->A,1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T. In someembodiments, the patient possesses a CFTR genetic mutation selected from2789+5G->A and 3272-26A->G.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from G178R, G551S,G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V,G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A,621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A,406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A,1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A,3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G,711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A,1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->Cand 621+3A->G, and human CFTR mutations selected from F508del, R117H,and G551D.

In some embodiments, in the methods of treating, lessening the severityof, or symptomatically treating cystic fibrosis disclosed herein, thepatient possesses a CFTR genetic mutation selected from G178R, G551S,G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V,G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G,S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A,621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A,406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A,1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A,3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G,711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A,1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T,4005+2T->C, 621+3A->G, and a CFTR mutation selected from F508del, R117H,and G551D; and a CFTR mutations selected from F508del, R117H, and G551D.

In some embodiments, the patient possesses a CFTR genetic mutationselected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R,S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selectedfrom F508del, R117H, and G551D. In some embodiments, the patientpossesses a CFTR genetic mutation selected from G178R, G551S, G970R,G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTRmutation selected from F508del, R117H, and G551D. In some embodiments,the patient possesses a CFTR genetic mutation selected from E193K,F1052V and G1069R, and a human CFTR mutation selected from F508del,R117H, and G551D.

In some embodiments, the patient possesses a CFTR genetic mutationselected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E,D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and ahuman CFTR mutation selected from F508del, R117H, and G551D.

In some embodiments, the patient possesses a CFTR genetic mutationselected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T,2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A,712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A,2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A,1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1717-8G->A, 1342-2A->C,405+3A->C, 1716G/A, 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A,1898+1G->T, 4005+2T->C and 621+3A->G, and a human CFTR mutation selectedfrom F508del, R117H, and G551D. In some embodiments, the patientpossesses a CFTR genetic mutation selected from 1717-1G->A,1811+1.6kbA->G, 2789+5G->A, 3272-26A->G and 3849+10kbC->T, and a humanCFTR mutation selected from F508del, R117H, and G551D. In someembodiments, the patient possesses a CFTR genetic mutation selected from2789+5G->A and 3272-26A->G, and a human CFTR mutation selected fromF508del, R117H.

In some embodiments, the patient is heterozygous having a CF-causingmutation on one allele and a CF-causing mutation on the other allele. Insome embodiments, the patient is heterozygous for F508del, and the otherCFTR genetic mutation is any CF-causing mutation, including, but notlimited to F508del on one CFTR allele and a CFTR mutation on the secondCFTR allele that is associated with minimal CFTR function, residual CFTRfunction, or a defect in CFTR channel gating activity.

In some embodiments, the CF-causing mutation is selected from Table A.In some embodiments, the CF-causing mutation is selected from Table B.In some embodiments, the CF-causing mutation is selected from Table C.In some embodiments, the CF-causing mutation is selected from FIG. 3. Insome embodiments, the patient is heterozygous having a CF-causingmutation on one CFTR allele selected from the mutations listed in thetable from FIG. 3 and a CF-causing mutation on the other CFTR allele isselected from the CFTR mutations listed in Table B:

TABLE B CFTR Mutations Q39X S1196X 4382delA W57X W1204X 4016insT E60XS1255X 2347delG R75X W1282X 3007delG E92X Q1313X 574delA Q98X 621 + 1G→T2711delT Y122X 711 + 1G→T 3791delC L218X 711 + 5G→A CFTRdele22-23 Q220X712-1G→T 457TAT→G C276X 405 + 1G→A 2043delG Q290X 405 + 3A→C 2869insGG330X 406-1G→A 3600 + 2insT W401X 621 + 1G→T 3737delA Q414X 1248 + 1G→A4040delA S434X 1341 + 1G→A 541delC S466X 1717 − 1G→A A46D S489X 1811 +1.6kbA→G T338I Q493X 1811 + 1G→C R347P W496X 1812 − 1G→A L927P Q525X1898 + 1G→A G85E G542X 2622 + 1G→A S341P Q552X 3120 + 1G→A L467P R553X3120G→A I507del E585X 3850 − 1G→A V520F G673X 4005 + 1G→A A559T R709X4374 + 1G→T R560T K710X 663delT R560S L732X 2183AA→G A561E R764XCFTRdel2,3 Y569D R785X 3659delC L1065P R792X 394delTT R1066C E822X2184insA R1066M W846X 3905insT L1077P R851X 2184delA H1085R Q890X1078delT M1101K S912X 1154insTC N1303K W1089X 2183delAA→G 3849 + 10kbC→TY1092X 2143delT 3272 − 26A→G E1104X 1677delTA 711 + 3A→G R1158X 3876delAE56K R1162X 2307insA P67L R74W E831X S549N D110E S945L S549R D110H S977FG551D R117C F1052V G551S L206W R1070W G1244E R347H F1074L S1251N R352QD1152H S1255P A455E D1270N G1349D D579G G178R

TABLE C CFTR Mutations Criteria Mutation Truncation mutations S4X C276XG542X R792X E1104X or nonsense mutations G27X Q290X G550X E822X R1158X %PI >50% and/or Q39X G330X Q552X W846X R1162X SwCl⁻ >86 mmol/L W57X W401XR553X Y849X S1196X no full-length E60X Q414X E585X R851X W1204X proteinR75X S434X G673X Q890X L1254X E92X S466X Q685X S912X S1255X Q98X S489XR709X Y913X W1282X Y122X Q493X K710X W1089X Q1313X E193X W496X L732XY1092X E1371X L218X C524X R764X W1098X Q1382X Q220X Q525X R785X R1102XQ1411X Splice mutations or 185 + 1G→T 711 + 5G→A 1717 − 8G→A 2622 + 1G→A3121 − 1G→A Carnonical splic 296 + 1G→A 712 − 1G→T 1717 − 1G→A 2790 −1G→C 3500 − 2A→G mutations 405 + 1G→A 1248 + 1G→A 1811 + 1G→C 3040G→C3600 + 2insT % PI >50% and/or 405 + 3A→C 1249 − 1G→A 1811 + 1.6kbA→G(G970R) 3850 − 1G→A SwCl⁻ >86 mmol/L 406 − 1G→A 1341 + 1G→A 1812 − 1G→A3120G→A 4005 + 1G→A no or little mature 621 + 1G→T 1525 − 2A→G 1898 +1G→A 3120 + 1G→A 4374 + 1G→T mRNA 711 + 1G→T 1525 − 1G→A 1898 + 1G→C3121 − 2A→G Small (≤3 nucleotide) 182delT 1119delA 1782delA 2732insA3876delA insertion/deletion 306insA 1138insG 1824delA 2869insG 3878delG(ins/del) frameshift 365-366insT 1154insTC 2043delG 2896insAG 3905insTmutations 394delTT 1161delC 2143delT 2942insT 4016insT % PI >50% and/or442delA 1213delT 2183AA→G^(a) 2957delT 4021dupT SwCl⁻ >86 mmol/L 444delA1259insA 2184delA 3007delG 4040delA garbled and/or 457TAT→G 1288insTA2184insA 3028delA 4279insA truncated protein 541delC 1471delA 2307insA3171delC 4326delTC 574delA 1497delGG 2347delG 3659delC 663delT 1548delG2585delT 3737delA 935delA 1609del CA 2594delGT 3791delC 1078delT1677delTA 2711delT 3821delT Non-small (>3 CFTRdele2,3 1461ins4 2991del32nucleotide) CFTRdele22,23 1924del7 3667ins4 insertion/deletion124del23bp 2055del9→A 4010del4 (ins/del) frameshift 852del222105-2117del13insAGAAA 4209TGTT→*AA mutations 991del5 2721del11 %PI >50% and/or SwCl⁻ >86 mmol/L garbled and/or truncated protein ClassII, III, IV A46D^(b) V520F Y569D^(b) N1303K mutations not G85E A559T^(b)L1065P responsive to R347P R560T R1066C Compound III alone L467P^(b)R560S L1077P^(b) or in combination I507del A561E M1101K with Compound IIor Compound IV/or Missense muatations that: % PI >50% and/or SwCl >86mmol/L AND Not responsive in vitro to Compound III alone or incombination with Compound II or Compound IV Note: % PI: percentage ofF508del-CFTR heterozygous patients in the CFTR2 patient registry who arepancreatic insufficient; SwCl⁻: mean sweat chloride of F508del-CFTRheterozygous patients in the CFTR2 patient registry ^(a)Also known as2183delAA→G. ^(b)Unpublished data.

In some embodiments, the patient is: with F508del/MF (F/MF) genotypes(heterozygous for F508del and an MF mutation not expected to respond toCFTR modulators, such as Compound III); with F508del/F508del(F/F)genotype (homozygous for F508del); and/or with F508del/gating (F/G)genotypes (heterozygous for F508del and a gating mutation known to beCFTR modulator-responsive (e.g., Compound III-responsive). In someembodiments, the patient with F508del/MF (F/MF) genotypes has a MFmutation that is not expected to respond to Compound II, Compound III,and both of Compound II and Compound III. In some embodiments, thepatient with F508del/MF (F/MF) genotypes has any one of the MF mutationsin Table C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any CF-causing mutation, includingtruncation mutations, splice mutations, small (≤3 nucleotide) insertionor deletion (ins/del) frameshift mutations; non-small (>3 nucleotide)insertion or deletion (ins/del) frameshift mutations; and Class II, III,IV mutations not responsive to Compound III alone or in combination withCompound II or Compound IV.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is a truncation mutation. In some specificembodiments, the truncation mutation is a truncation mutation listed inTable C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is a splice mutation. In some specificembodiments, the splice mutation is a splice mutation listed in Table C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is a small (≤3 nucleotide) insertion ordeletion (ins/del) frameshift mutation. In some specific embodiments,the small (≤3 nucleotide) insertion or deletion (ins/del) frameshiftmutation is a small (≤3 nucleotide) insertion or deletion (ins/del)frameshift mutation listed in Table C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any CF-causing mutation expected to beand/or is responsive to, based on in vitro and/or clinical data, anycombination of (i) a novel compound chosen from those disclosed herein(e.g., compounds of Formula (I), (II), (III), (IV), or (V), andpharmaceutically acceptable salts thereof, and their deuteratedderivatives), and (ii) Compound II, and/or Compound III, and/or CompoundIV.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any CF-causing mutation expected to beand/or is responsive, based on in vitro and/or clinical data, to thetriple combination of a novel compound chosen from those disclosedherein (e.g., compounds of Formula (I), (II), (III), (IV), or (V), andpharmaceutically acceptable salts thereof, and their deuteratedderivatives), and Compound II, and Compound III.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is a non-small (>3 nucleotide) insertion ordeletion (ins/del) frameshift mutation. In some specific embodiments,the non-small (>3 nucleotide) insertion or deletion (ins/del) frameshiftmutation is a non-small (>3 nucleotide) insertion or deletion (ins/del)frameshift mutation listed in Table 5B.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is a Class II, III, IV mutations notresponsive to Compound III alone or in combination with Compound II orCompound IV. In some specific embodiments, the Class II, III, IVmutations not responsive to Compound III alone or in combination withCompound II or Compound IV is a Class II, III, IV mutations notresponsive to Compound III alone or in combination with Compound II orCompound IV listed in Table C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any mutation listed in Table C.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any mutation, but other than F508del,listed in Table A, B, C, and FIG. 3.

In some embodiments, the patient is heterozygous for F508del, and theother CFTR genetic mutation is any mutation listed in Table A. In someembodiments, the patient is heterozygous for F508del, and the other CFTRgenetic mutation is any mutation listed in Table B. In some embodiments,the patient is heterozygous for F508del, and the other CFTR geneticmutation is any mutation listed in Table C. In some embodiments, thepatient is heterozygous for F508del, and the other CFTR genetic mutationis any mutation listed in FIG. 3.

In some embodiments, the patient is homozygous for F508del.

In some embodiments, the patient is heterozygous having one CF-causingmutation on one CFTR allele selected from the mutations listed in thetable from FIG. 3 and another CF-causing mutation on the other CFTRallele is selected from the CFTR mutations listed in Table C.

In some embodiments, the composition disclosed herein is useful fortreating, lessening the severity of, or symptomatically treating cysticfibrosis in patients who exhibit residual CFTR activity in the apicalmembrane of respiratory and non-respiratory epithelia. The presence ofresidual CFTR activity at the epithelial surface can be readily detectedusing methods known in the art, e.g., standard electrophysiological,biochemical, or histochemical techniques. Such methods identify CFTRactivity using in vivo or ex vivo electrophysiological techniques,measurement of sweat or salivary Cl⁻ concentrations, or ex vivobiochemical or histochemical techniques to monitor cell surface density.Using such methods, residual CFTR activity can be readily detected forpatients that are heterozygous or homozygous for a variety of differentmutations, including patients heterozygous for the most common mutation,F508del, as well as other mutations such as the G551D mutation, or theR117H mutation. In some embodiments, compositions disclosed herein areuseful for treating, lessening the severity of, or symptomaticallytreating cystic fibrosis in patients who exhibit little to no residualCFTR activity. In some embodiments, compositions disclosed herein areuseful for treating, lessening the severity of, or symptomaticallytreating cystic fibrosis in patients who exhibit little to no residualCFTR activity in the apical membrane of respiratory epithelia.

In some embodiments, the compositions disclosed herein are useful fortreating or lessening the severity of cystic fibrosis in patients whoexhibit residual CFTR activity using pharmacological methods. Suchmethods increase the amount of CFTR present at the cell surface, therebyinducing a hitherto absent CFTR activity in a patient or augmenting theexisting level of residual CFTR activity in a patient.

In some embodiments, the compositions disclosed herein are useful fortreating or lessening the severity of cystic fibrosis in patients withcertain genotypes exhibiting residual CFTR activity.

In some embodiments, compositions disclosed herein are useful fortreating, lessening the severity of, or symptomatically treating cysticfibrosis in patients within certain clinical phenotypes, e.g., a mild tomoderate clinical phenotype that typically correlates with the amount ofresidual CFTR activity in the apical membrane of epithelia. Suchphenotypes include patients exhibiting pancreatic sufficiency.

In some embodiments, the compositions disclosed herein are useful fortreating, lessening the severity of, or symptomatically treatingpatients diagnosed with pancreatic sufficiency, idiopathic pancreatitisand congenital bilateral absence of the vas deferens, or mild lungdisease wherein the patient exhibits residual CFTR activity.

In some embodiments, this disclosure relates to a method of augmentingor inducing anion channel activity in vitro or in vivo, comprisingcontacting the channel with a composition disclosed herein. In someembodiments, the anion channel is a chloride channel or a bicarbonatechannel. In some embodiments, the anion channel is a chloride channel.

In some embodiments of the methods of treating cystic fibrosis disclosedherein, the absolute change in patient's percent predicted forcedexpiratory volume in one second (ppFEV₁) after 15 days of administrationof at least one compound chosen from Compound I and pharmaceuticallyacceptable salts thereof, at least one compound chosen from Compound IIand pharmaceutically acceptable salts thereof, and at least one compoundchosen from Compound III or III-d and pharmaceutically acceptable saltsthereof ranges from 3% to 40% relative to the ppFEV1 of the patientprior to said administration.

In some embodiments of the methods of treating cystic fibrosis disclosedherein, the absolute change in patient's percent predicted forcedexpiratory volume in one second (ppFEV₁) after 29 days of administrationof at least one compound chosen from Compound I and pharmaceuticallyacceptable salts thereof, at least one compound chosen from Compound IIand pharmaceutically acceptable salts thereof, and at least one compoundchosen from Compound III and pharmaceutically acceptable salts thereofranges from 3% to 40% relative to the ppFEV1 of the patient prior tosaid administration.

In some embodiments of the methods of treating cystic fibrosis disclosedherein, the absolute change in the patient's sweat chloride after 15days of administration of at least one compound chosen from Compound Iand pharmaceutically acceptable salts thereof, at least one compoundchosen from Compound II and pharmaceutically acceptable salts thereof,and at least one compound chosen from Compound III or III-d andpharmaceutically acceptable salts thereof ranges from −2 to −65 mmol/Lfrom baseline, i.e., relative to the sweat chloride of the patient priorto said administration. In some embodiments, the absolute change insweat chloride of said patient ranges from −5 to −65 mmol/L. In someembodiments, the absolute change in sweat chloride of said patientranges from −10 to −65 mmol/L. In some embodiments, the absolute changein sweat chloride of said patient ranges from −2 to −65 mmol/L.

In some embodiments of the methods of treating cystic fibrosis disclosedherein, the absolute change in the patient's sweat chloride after 29days of administration of at least one compound chosen from Compound Iand pharmaceutically acceptable salts thereof, at least one compoundchosen from Compound II and pharmaceutically acceptable salts thereof,and at least one compound chosen from Compound III and pharmaceuticallyacceptable salts thereof ranges from −2 to −65 mmol/L from baseline,i.e., relative to the sweat chloride of the patient prior to saidadministration. In some embodiments, the absolute change in sweatchloride of said patient ranges from −5 to −65 mmol/L. In someembodiments, the absolute change in sweat chloride of said patientranges from −10 to −65 mmol/L. In some embodiments, the absolute changein sweat chloride of said patient ranges from −2 to −65 mmol/L.

In some embodiments, the triple combinations are administered to apatient who has one F508del mutation and one minimal function mutation,and who has not taken any of said at least one compound chosen fromCompound I and pharmaceutically acceptable salts thereof, at least onecompound chosen from Compound II and pharmaceutically acceptable saltsthereof, and at least one compound chosen from Compound III or III-d andpharmaceutically acceptable salts thereof.

In some embodiments, the triple combinations are administered to apatient has two copies of F508del mutation, and wherein patient hastaken at least one compound chosen from Compound II and pharmaceuticallyacceptable salts thereof, and at least one compound chosen from CompoundIII or III-d and pharmaceutically acceptable salts thereof, but not anyof said at least one compound chosen from Compound I andpharmaceutically acceptable salts thereof.

In some embodiments, the absolute change in patient's ppFEV₁ after 15days of administration of at least one compound chosen from Compound Iand pharmaceutically acceptable salts thereof, at least one compoundchosen from Compound II and pharmaceutically acceptable salts thereof,and at least one compound chosen from Compound III or III-d andpharmaceutically acceptable salts thereof ranges from 3% to 35% relativeto the ppFEV1 of the patient prior to said administration.

In some embodiments, the absolute change in patient's ppFEV₁ after 29days of administration of at least one compound chosen from Compound Iand pharmaceutically acceptable salts thereof, at least one compoundchosen from Compound II and pharmaceutically acceptable salts thereof,and at least one compound chosen from Compound III and pharmaceuticallyacceptable salts thereof ranges from 3% to 35% relative to the ppFEV1 ofthe patient prior to said administration.

In some embodiments, the absolute change in a patient's ppFEV₁ relativeto the ppFEV1 of the patient prior to such administration of the triplecombinations can be calculated as (postbaseline value-baseline value).The baseline value is defined as the most recent non-missing measurementcollected before the first dose of study drug in the Treatment Period(Day 1).

The exact amount of API(s) and tablets comprising such API(s) requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the disease, theparticular agent, its mode of administration, and the like. Thecompounds of this disclosure may be formulated in dosage unit form forease of administration and uniformity of dosage. The expression “dosageunit form” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of API(s) and tablets comprisingsuch API(s) of this disclosure will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific API employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed, and like factors well known in themedical arts. The term “patient”, as used herein, means an animal, suchas a mammal, and even further such as a human.

In some embodiments, the disclosure also is directed to methods oftreatment using isotope-labelled compounds of the afore-mentionedcompounds, which have the same structures as disclosed herein exceptthat one or more atoms therein have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally (isotopelabelled). Examples of isotopes which are commercially available andsuitable for the disclosure include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.

The isotope-labelled compounds and salts can be used in a number ofbeneficial ways. They can be suitable for medicaments and/or varioustypes of assays, such as substrate tissue distribution assays. Forexample, tritium (³H)- and/or carbon-14 (¹⁴C)-labelled compounds areparticularly useful for various types of assays, such as substratetissue distribution assays, due to relatively simple preparation andexcellent detectability. For example, deuterium (²H)-labelled ones aretherapeutically useful with potential therapeutic advantages over thenon-²H-labelled compounds. In general, deuterium (²H)-labelled compoundsand salts can have higher metabolic stability as compared to those thatare not isotope-labelled owing to the kinetic isotope effect describedbelow. Higher metabolic stability translates directly into an increasedin vivo half-life or lower dosages, which could be desired. Theisotope-labelled compounds and salts can usually be prepared by carryingout the procedures disclosed in the synthesis schemes and the relateddescription, in the example part and in the preparation part in thepresent text, replacing a non-isotope-labelled reactant by a readilyavailable isotope-labelled reactant.

In some embodiments, the isotope-labelled compounds and salts aredeuterium (²H)-labelled ones. In some specific embodiments, theisotope-labelled compounds and salts are deuterium (²H)-labelled,wherein one or more hydrogen atoms therein have been replaced bydeuterium. In chemical structures, deuterium is represented as “²H” or“D.”

The deuterium (²H)-labelled compounds and salts can manipulate theoxidative metabolism of the compound by way of the primary kineticisotope effect. The primary kinetic isotope effect is a change of therate for a chemical reaction that results from exchange of isotopicnuclei, which in turn is caused by the change in ground state energiesnecessary for covalent bond formation after this isotopic exchange.Exchange of a heavier isotope usually results in a lowering of theground state energy for a chemical bond and thus causes a reduction inthe rate-limiting bond breakage. If the bond breakage occurs in or inthe vicinity of a saddle-point region along the coordinate of amulti-product reaction, the product distribution ratios can be alteredsubstantially. For explanation: if deuterium is bonded to a carbon atomat a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. For a further discussion, see S. L. Harbeson and R. D. Tung,Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011,46, 403-417; and T. G. Gant “Using deuterium in drug discovery: leavingthe label in the drug” J. Med. Chem. 2014, 57, 3595-3611, relevantportions of which are independently incorporated herein by reference.

The concentration of the isotope(s) (e.g., deuterium) incorporated intothe isotope-labelled compounds and salt of the disclosure may be definedby the isotopic enrichment factor. The term “isotopic enrichment factor”as used herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. In some embodiments, if asubstituent in a compound of the disclosure is denoted deuterium, suchcompound has an isotopic enrichment factor for each designated deuteriumatom of at least 3500 (52.5% deuterium incorporation at each designateddeuterium atom), at least 4000 (60% deuterium incorporation), at least4500 (67.5% deuterium incorporation), at least 5000 (75% deuteriumincorporation), at least 5500 (82.5% deuterium incorporation), at least6000 (90% deuterium incorporation), at least 6333.3 (95% deuteriumincorporation), at least 6466.7 (97% deuterium incorporation), at least6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It may be reasonable to assumethat many compounds with poor pharmacokinetic profiles are susceptibleto oxidative metabolism.

One of ordinary skill in the art would understand that deuteration ofone or more metabolically labile positions on a compound or activemetabolite may lead to improvement of one or more superior DMPKproperties while maintaining biological activity as compared to thecorresponding hydrogen analogs. The superior DMPK property or propertiesmay have an impact on the exposure, half-life, clearance, metabolism,and/or even food requirements for optimal absorption of the drugproduct. Deuteration may also change the metabolism at othernon-deuterated positions of the deuterated compound.

Compound III-d as used herein includes the deuterated compound disclosedin U.S. Pat. No. 8,865,902 (which is incorporated herein by reference),and CTP-656.

As mentioned above, Compound III-d is:

Exemplary embodiments of the disclosure include:

1. A single tablet comprising

(a) 25 mg to 150 mg of Compound I:

(b) a first solid dispersion comprising 20 mg to 150 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 25 mg to 200 mg of CompoundIII-d:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.2. The single tablet of embodiment 1, wherein at least one of the firstor second solid dispersions is a spray-dried dispersion.3. The single tablet of embodiment 1, wherein both of the first andsecond solid dispersions are spray-dried dispersions.4. The single tablet of embodiment 1, wherein said polymer in the firstsolid dispersion is hydroxypropyl methylcellulose; and said polymer inthe second solid dispersion is hydroxypropyl methylcellulose acetatesuccinate.5. The single tablet of embodiment 1, wherein said polymer in the firstsolid dispersion is HPMC E15; and said polymer in the second soliddispersion is hydroxypropyl methylcellulose acetate succinate H.6. The single tablet of embodiment 1, wherein said polymer in the firstsolid dispersion is HPMC E15; and said polymer in the second soliddispersion is hydroxypropyl methylcellulose acetate succinate HG.6a. The single tablet of embodiment 1, wherein Compound I is CrystallineForm A.6b. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is in substantially pure form.6c. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractogram having a signalat at least three two-theta values chosen from 6.6±0.2, 7.6±0.2,9.6±0.2, 12.4±0.2, 13.1±0.2, 15.2±0.2, 16.4±0.2, 18.2±0.2, and 18.6±0.2.6d. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractograph having asignal at at least three two-theta values chosen from 6.6±0.2, 9.6±0.2,7.6±0.2, 15.2±0.2, 12.4±0.2, and 16.4±0.2.6e. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractograph having asignal at three two-theta values of 6.6±0.2, 9.6±0.2, 15.2±0.2.6f. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractograph having asignal at six two-theta values of 6.6±0.2, 9.6±0.2, 7.6±0.2, 15.2±0.2,12.4±0.2, and 16.4±0.2.6g. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractogram substantiallysimilar to that in FIG. 4A.6h. The single tablet of embodiment 6a, wherein Compound I CrystallineForm A is characterized by an X-ray powder diffractogram substantiallysimilar to that in FIG. 4B.7. The single tablet of any one of embodiments 1-6g, comprising 80 mg to120 mg of Compound I.8. The single tablet of any one of embodiments 1-6g, comprising 80 mg to120 mg, 85 mg to 115 mg, 90 mg to 110 mg, or 95 mg to 105 mg of CompoundI.9. The single tablet of any one of embodiments 1-6g, comprising 100 mgof Compound I.10. The single tablet of any one of embodiments 1-6g, comprising 75 mgto 125 mg of Compound I.11. The single tablet of any one of embodiments 1-10, wherein the firstsolid dispersion comprises 25 mg to 75 mg of Compound II.12. The single tablet of any one of embodiments 1-10, wherein the firstsolid dispersion comprises 50 mg of Compound II.13. The single tablet of any one of embodiments 1-12, wherein the secondsolid dispersion comprises 25 mg to 50 mg, 25 mg to 75 mg, 50 mg to 100mg, or 75 mg to 125 mg of Compound III-d.14. The single tablet of any one of embodiments 1-12, wherein the secondsolid dispersion comprises 75 mg of Compound III-d.15. The single tablet of any one of embodiments 1-6, comprising50 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg to 75 mg of Compound II; andthe second solid dispersion comprises 75 mg to 125 mg of Compound III-d.16. The single tablet of any one of embodiments 1-6, comprising75 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III-d.17. The single tablet of any one of embodiments 1-6, comprising100 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III-d.18. The single tablet of any one of embodiments 1-17, wherein the secondsolid dispersion further comprises 0.5% sodium lauryl sulfate relativeto the total weight of the second solid dispersion.19. The single tablet of any one of embodiments 1-18, further comprisingone or more pharmaceutically acceptable excipients chosen from one ormore fillers, disintegrants, lubricants, and glidants.20. The single tablet of embodiment 19, wherein fillers are chosen frommicrocrystalline cellulose, silicified microcrystalline cellulose,lactose monohydrate, dicalcium phosphate, mannitol, copovidone,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum.21. The single tablet of embodiment 19, wherein disintegrants are chosenfrom croscarmellose sodium, sodium starch glycolate, crospovidone, cornor pre-gelatinized starch, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, and microcrystalline cellulose.22. The single tablet of embodiment 19, wherein lubricants are chosenfrom magnesium stearate, sodium stearyl fumarate, calcium stearate,sodium stearate, stearic acid, and talc.23. The single tablet of embodiment 19, wherein glidants are colloidalsilicon dioxide.24. The single tablet of any one of embodiments 1-23, wherein Compound Iis substantially crystalline, and wherein each of Compounds II and III-dare independently substantially amorphous.25. A pharmaceutical composition comprising:

(a) 10 wt % to 30 wt % of Compound I:

relative to the total weight of the pharmaceutical composition;(b) 10 wt % to 30 wt % of a first solid dispersion relative to the totalweight of the pharmaceutical composition,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) 10 wt % to 30 wt % of a second solid dispersion relative to thetotal weight of the pharmaceutical composition;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.26. The pharmaceutical composition of embodiment 25, wherein at leastone of the first or second solid dispersions is a spray-drieddispersion.27. The pharmaceutical composition of embodiment 25, wherein both of thefirst and second solid dispersions are spray-dried dispersions.28. The pharmaceutical composition of embodiment 25, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.29. The pharmaceutical composition of embodiment 25, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.30. The pharmaceutical composition of embodiment 25, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of CompoundIII-d relative to the total weight of the second solid dispersion, 0.5%sodium lauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.31. The pharmaceutical composition of any one of embodiments 25-30,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.32. The pharmaceutical composition of any one of embodiments 25-31,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.33. The pharmaceutical composition of any one of embodiments 25-32,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III-d relative to the total weight of the second soliddispersion.34. The pharmaceutical composition of any one of embodiments 25-33,wherein the second solid dispersion comprises 80 wt % of Compound III-drelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.35. The pharmaceutical composition of any one of embodiments 25-34,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.36. The pharmaceutical composition of embodiment 35, wherein fillers arechosen from microcrystalline cellulose, silicified microcrystallinecellulose, lactose monohydrate, dicalcium phosphate, mannitol,copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guargum.37. The pharmaceutical composition of embodiment 35, whereindisintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose.38. The pharmaceutical composition of embodiment 35, wherein lubricantsare chosen from magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, and talc.39. The pharmaceutical composition of embodiment 35, wherein glidantsare colloidal silicon dioxide.40. The pharmaceutical composition of any one of embodiments 25-39,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III-d is independently substantially amorphous.41. The pharmaceutical composition of any one of embodiments 25-40,wherein the pharmaceutical composition is a tablet.42. The pharmaceutical composition of any one of embodiments 25-40,wherein the pharmaceutical composition is in the form of granules.43. A pharmaceutical composition comprising:

(a) Compound I:

(b) a first solid dispersion,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer; and(c) a second solid dispersion;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer, whereinThe weight ratio of Compound I in (a):Compound II in (b):Compound III-din (c) ranges from 1-4:2:3.43a. The pharmaceutical composition of embodiment 43, wherein the weightratio of Compound I in (a):Compound II in (b):Compound III-d in (c) is2:2:3.43b. The pharmaceutical composition of embodiment 43, wherein the weightratio of Compound I in (a):Compound II in (b):Compound III-d in (c) is1:2:3.43c. The pharmaceutical composition of embodiment 43, wherein the weightratio of Compound I in (a):Compound II in (b):Compound III-d in (c) is4:2:3.44. The pharmaceutical composition of embodiment 43, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.45. The pharmaceutical composition of embodiment 43, wherein both of thefirst and second solid dispersions are spray-dried dispersions.46. The pharmaceutical composition of embodiment 43, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.47. The pharmaceutical composition of embodiment 43, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.48. The pharmaceutical composition of embodiment 43, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of CompoundIII-d relative to the total weight of the second solid dispersion, 0.5%sodium lauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.49. The pharmaceutical composition of any one of embodiments 43-48,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.50. The pharmaceutical composition of any one of embodiments 43-49,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.51. The pharmaceutical composition of any one of embodiments 43-50,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III-d relative to the total weight of the second soliddispersion.52. The pharmaceutical composition of any one of embodiments 43-51,wherein the second solid dispersion comprises 80 wt % of Compound III-drelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.53. The pharmaceutical composition of any one of embodiments 43-42,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.54. The pharmaceutical composition of embodiment 53, wherein fillers arechosen from microcrystalline cellulose, silicified microcrystallinecellulose, lactose monohydrate, dicalcium phosphate, mannitol,copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guargum.55. The pharmaceutical composition of embodiment 53, whereindisintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose.56. The pharmaceutical composition of embodiment 53, wherein lubricantsare chosen from magnesium stearate, sodium stearyl fumarate, calciumstearate, sodium stearate, stearic acid, and talc.57. The pharmaceutical composition of embodiment 53, wherein glidantsare colloidal silicon dioxide.58. The pharmaceutical composition of any one of embodiments 43-57,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III-d is independently substantially amorphous.59. The pharmaceutical composition of any one of embodiments 43-58,wherein the pharmaceutical composition is a tablet.60. The pharmaceutical composition of any one of embodiments 43-58,wherein the pharmaceutical composition is in the form of granules.61. A single tablet comprising:

(a) 25 mg to 125 mg of Compound I:

(b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt %Compound II relative to the total weight of the first solid dispersion:

and 20 wt % of a hydroxypropyl methylcellulose relative to the totalweight of the first solid dispersion; and(c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

0.5 wt % of sodium lauryl sulfate relative to the total weight of thesecond solid dispersion; and 19.5 wt % of a hydroxypropylmethylcellulose acetate succinate to the total weight of the secondsolid dispersion(d) 75 mg to 230 mg of microcrystalline cellulose;(e) 20 mg to 45 mg of croscarmellose sodium; and(f) 2 mg to 7 mg of magnesium stearate.62. The single tablet of embodiment 61, wherein the tablet comprises anintra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 75 mg to 85 mg of said microcrystalline cellulose;(e) 25 mg to 35 mg of said croscarmellose sodium; and(B) wherein the extra-granular part comprises:(a) 115 mg to 120 mg of said microcrystalline cellulose; and(b) 3 mg to 7 mg of magnesium stearate.63. The single tablet of embodiment 61, wherein the tablet comprises anintra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium; and(B) wherein the extra-granular part comprises:(a) 85 mg to 95 mg of said microcrystalline cellulose; and(b) 2 mg to 6 mg of magnesium stearate.64. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 200 mg of said microcrystalline cellulose; and(f) 3 mg to 7 mg of magnesium stearate.65. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.66. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.67. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 35 mg to 40 mg of said croscarmellose sodium;(e) 105 mg to 115 mg of lactose monohydrate;(f) 220 mg to 230 mg of said microcrystalline cellulose;(g) 1 mg to 5 mg of colloidal silicon dioxide; and(h) 4 mg to 7 mg of magnesium stearate.68. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 40 mg to 50 mg of lactose monohydrate;(f) 90 mg to 100 mg of said microcrystalline cellulose;(g) 1 mg to 5 mg of colloidal silicon dioxide; and(h) 2 mg to 7 mg of magnesium stearate.69. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose;(f) 1 mg to 5 mg of colloidal silicon dioxide; and(g) 2 mg to 7 mg of magnesium stearate.70. The single tablet of embodiment 61, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.71. A single tablet comprising

(a) 25 mg to 150 mg of Compound I:

(b) a first solid dispersion comprising 20 mg to 150 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 25 mg to 200 mg of CompoundIII:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.72. The single tablet of embodiment 71, wherein at least one of thefirst or second solid dispersions is a spray-dried dispersion.73. The single tablet of embodiment 71, wherein both of the first andsecond solid dispersions are spray-dried dispersions.74. The single tablet of embodiment 71, wherein said polymer in thefirst solid dispersion is hydroxypropyl methylcellulose; and saidpolymer in the second solid dispersion is hydroxypropyl methylcelluloseacetate succinate.75. The single tablet of embodiment 71, wherein said polymer in thefirst solid dispersion is HPMC E15; and said polymer in the second soliddispersion is hydroxypropyl methylcellulose acetate succinate H.76. The single tablet of embodiment 71, wherein said polymer in thefirst solid dispersion is HPMC E15; and said polymer in the second soliddispersion is hydroxypropyl methylcellulose acetate succinate HG.77. The single tablet of any one of embodiments 71-76, comprising 80 mgto 120 mg of Compound I.78. The single tablet of any one of embodiments 71-76, comprising 80 mgto 120 mg, 85 mg to 115 mg, 90 mg to 110 mg, or 95 mg to 105 mg ofCompound I.79. The single tablet of any one of embodiments 71-76, comprising 100 mgof Compound I.80. The single tablet of any one of embodiments 71-76, comprising 75 mgto 125 mg of Compound I.81. The single tablet of any one of embodiments 71-80, wherein the firstsolid dispersion comprises 25 mg to 75 mg of Compound II.82. The single tablet of any one of embodiments 71-80, wherein the firstsolid dispersion comprises 50 mg of Compound II.83. The single tablet of any one of embodiments 71-82, wherein thesecond solid dispersion comprises 25 mg to 50 mg, 25 mg to 75 mg, 50 mgto 100 mg, or 75 mg to 125 mg of Compound III.84. The single tablet of any one of embodiments 71-82, wherein thesecond solid dispersion comprises 75 mg of Compound III.85. The single tablet of any one of embodiments 71-76, comprising50 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg to 75 mg of Compound II; andthe second solid dispersion comprises 75 mg to 125 mg of Compound III.86. The single tablet of any one of embodiments 71-82, comprising75 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III.87. The single tablet of any one of embodiments 71-82, comprising100 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III.88. The single tablet of any one of embodiments 71-87, wherein thesecond solid dispersion further comprises 0.5% sodium lauryl sulfaterelative to the total weight of the second solid dispersion.89. The single tablet of any one of embodiments 71-88, furthercomprising one or more pharmaceutically acceptable excipients chosenfrom one or more fillers, disintegrants, lubricants, and glidants.90. The single tablet of embodiment 89, wherein fillers are chosen frommicrocrystalline cellulose, silicified microcrystalline cellulose,lactose monohydrate, dicalcium phosphate, mannitol, copovidone,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum.91. The single tablet of embodiment 89, wherein disintegrants are chosenfrom croscarmellose sodium, sodium starch glycolate, crospovidone, cornor pre-gelatinized starch, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, and microcrystalline cellulose.92. The single tablet of embodiment 89, wherein lubricants are chosenfrom magnesium stearate, sodium stearyl fumarate, calcium stearate,sodium stearate, stearic acid, and talc.93. The single tablet of embodiment 89, wherein glidants are colloidalsilicon dioxide.94. The single tablet of any one of embodiments 71-93, wherein CompoundI is substantially crystalline, and wherein each of Compounds II and IIIare independently substantially amorphous.95. A pharmaceutical composition comprising:

(a) 10 wt % to 30 wt % of Compound I:

relative to the total weight of the pharmaceutical composition;(b) 8 wt % to 30 wt % of a first solid dispersion relative to the totalweight of the pharmaceutical composition,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) 10 wt % to 30 wt % of a second solid dispersion relative to thetotal weight of the pharmaceutical composition;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.96. The pharmaceutical composition of embodiment 95, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.97. The pharmaceutical composition of embodiment 95, wherein both of thefirst and second solid dispersions are spray-dried dispersions.98. The pharmaceutical composition of embodiment 95, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.99. The pharmaceutical composition of embodiment 95, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.100. The pharmaceutical composition of embodiment 95, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of Compound IIIrelative to the total weight of the second solid dispersion, 0.5% sodiumlauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.101. The pharmaceutical composition of any one of embodiments 95-100,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.102. The pharmaceutical composition of any one of embodiments 95-100,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.103. The pharmaceutical composition of any one of embodiments 95-102,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III relative to the total weight of the second soliddispersion.104. The pharmaceutical composition of any one of embodiments 95-103,wherein the second solid dispersion comprises 80 wt % of Compound IIIrelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.105. The pharmaceutical composition of any one of embodiments 95-104,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, and lubricants.106. The pharmaceutical composition of embodiment 105, wherein fillersare chosen from microcrystalline cellulose, silicified microcrystallinecellulose, lactose, dicalcium phosphate, mannitol, copovidone,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum.107. The pharmaceutical composition of embodiment 105, whereindisintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose.108. The pharmaceutical composition of embodiment 105, whereinlubricants are chosen from magnesium stearate, sodium stearyl fumarate,calcium stearate, sodium stearate, stearic acid, and talc.109. The pharmaceutical composition of any one of embodiments 95-108,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III is independently substantially amorphous.110. The pharmaceutical composition of any one of embodiments 95-109,wherein the pharmaceutical composition is a tablet.111. The pharmaceutical composition of any one of embodiments 95-109,wherein the pharmaceutical composition is in the form of granules.112. A pharmaceutical composition comprising:

(a) Compound I:

(b) a first solid dispersion comprising 70 wt % to 90 wt % of CompoundII relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 70 wt % to 90 wt % of CompoundIII relative to the total weight of the second solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion, whereinthe weight ratio of Compound I in (a):Compound II in (b):Compound III-din (c) ranges from 2:4:5 to 6:1:1.113. The pharmaceutical composition of embodiment 112, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.114. The pharmaceutical composition of embodiment 112, wherein both ofthe first and second solid dispersions are spray-dried dispersions.115. The pharmaceutical composition of embodiment 112, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.116. The pharmaceutical composition of embodiment 112, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.117. The pharmaceutical composition of embodiment 112, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of Compound IIIrelative to the total weight of the second solid dispersion, 0.5% sodiumlauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.118. The pharmaceutical composition of any one of embodiments 112-117,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.119. The pharmaceutical composition of any one of embodiments 112-117,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.120. The pharmaceutical composition of any one of embodiments 112-119,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III relative to the total weight of the second soliddispersion.121. The pharmaceutical composition of any one of embodiments 112-120,wherein the second solid dispersion comprises 80 wt % of Compound IIIrelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.122. The pharmaceutical composition of any one of embodiments 112-121,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, and lubricants.123. The pharmaceutical composition of embodiment 122, wherein fillersare chosen from microcrystalline cellulose, silicified microcrystallinecellulose, lactose, dicalcium phosphate, mannitol, copovidone,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, starch, Maltodextrin, agar, and guar gum.124. The pharmaceutical composition of embodiment 122, whereindisintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose.125. The pharmaceutical composition of embodiment 122, whereinlubricants are chosen from magnesium stearate, sodium stearyl fumarate,calcium stearate, sodium stearate, stearic acid, and talc.126. The pharmaceutical composition of any one of embodiments 112-125,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III is independently substantially amorphous.127. The pharmaceutical composition of any one of embodiments 112-126,wherein the pharmaceutical composition is a tablet.128. The pharmaceutical composition of any one of embodiments 112-126,wherein the pharmaceutical composition is in the form of granules.129. A single tablet comprising:

(a) 25 mg to 125 mg of Compound I:

(b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt %Compound II relative to the total weight of the first solid dispersion:

and 20 wt % of a hydroxypropyl methylcellulose relative to the totalweight of the first solid dispersion; and(c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt % ofCompound III relative to the total weight of the second soliddispersion:

0.5 wt % of sodium lauryl sulfate relative to the total weight of thesecond solid dispersion; and 19.5 wt % of a hydroxypropylmethylcellulose acetate succinate to the total weight of the secondsolid dispersion(d) 85 mg to 275 mg of microcrystalline cellulose;(e) 10 mg to 35 mg of croscarmellose sodium; and(f) 2 mg to 7 mg of magnesium stearate.130. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 75 mg to 85 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:(a) 115 mg to 120 mg of said microcrystalline cellulose; and(b) 3 mg to 7 mg of magnesium stearate.131. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 90 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:(a) 115 mg to 120 mg of microcrystalline cellulose; and(b) 2 mg to 7 mg of magnesium stearate.132. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium; and(B) wherein the extra-granular part comprises:(a) 85 mg to 95 mg of microcrystalline cellulose; and(b) 2 mg to 6 mg of magnesium stearate.133. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium; and(B) wherein the extra-granular part comprises:(a) 270 mg to 275 mg of microcrystalline cellulose; and(b) 2 mg to 7 mg of magnesium stearate.134. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 90 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:(a) 5 mg to 10 mg of said croscarmellose sodium;(b) 105 mg to 115 mg of microcrystalline cellulose; and(c) 2 mg to 7 mg of magnesium stearate.135. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 105 mg to 115 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:(a) 25 mg to 35 mg of said croscarmellose sodium;(b) 85 mg to 90 mg of microcrystalline cellulose; and(c) 2 mg to 7 mg of magnesium stearate.136. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 195 mg to 200 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:(a) 25 mg to 35 mg of said croscarmellose sodium; and(b) 2 mg to 7 mg of magnesium stearate.137. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:(a) 60 mg to 65 mg of said first solid dispersion;(b) 90 mg to 95 mg of said second solid dispersion;(c) 12 mg to 17 mg of said croscarmellose sodium;(d) 60 mg to 70 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 95 mg to 105 mg of microcrystalline cellulose; and(c) 2 mg to 7 mg of magnesium stearate.138. The single tablet of embodiment 129, wherein the tablet comprisesan intra-granular part and extra-granular part, and(A) wherein the intra-granular part comprises:(a) 60 mg to 65 mg of said first solid dispersion;(b) 90 mg to 95 mg of said second solid dispersion;(c) 10 mg to 20 mg of said croscarmellose sodium;(d) 60 mg to 70 mg of said microcrystalline cellulose; and(B) wherein the extra-granular part comprises:

(a) 90 mg to 110 mg of Compound I;

(b) 195 mg to 205 mg of microcrystalline cellulose; and(c) 2 mg to 7 mg of magnesium stearate.139. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.140. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 200 mg to 210 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.141. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.142. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 270 mg to 275 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.143. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.144. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.145. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 200 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.146. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 12 mg to 17 mg of said croscarmellose sodium;(e) 160 mg to 170 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.147. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 10 mg to 20 mg of said croscarmellose sodium;(e) 260 mg to 270 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.148. A pharmaceutical composition comprising(a) 10 wt % to 30 wt % Compound I relative to the total weight of thepharmaceutical composition:

(b) 5 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition:

(c) 10 wt % to 25 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition:

(d) 20 wt % to 45 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-8 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 2 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.149. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 18% to 23 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 8 wt % to 12 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 13 wt % to 18 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 35 wt % to 45 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.150. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 15% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 5 wt % to 10 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 7 wt % to 15 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 30 wt % to 50 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.151. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 20% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 15 wt % to 20 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 15 wt % to 25 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.152. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 20% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 15 wt % to 20 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 25 wt % to 35 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.153. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 22% to 28 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 10 wt % to 15 wt % of Compound II relative to the total weight ofthe pharmaceutical composition;(c) 15 wt % to 25 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 15 wt % to 25 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.154. The pharmaceutical composition of embodiment 148, wherein thepharmaceutical composition comprises:(a) 15% to 20 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 10 wt % to 15 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 45 wt % to 55 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-5 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.155. The pharmaceutical composition of any one of embodiments 148-154,wherein the pharmaceutical composition is a tablet.156. A method of treating cystic fibrosis in a patient comprising orallyadministering to the patient one or more of the single tablet orpharmaceutical composition of any one of embodiments 1-155.157. The method of embodiment 156, wherein one or more of the singletablets or pharmaceutical compositions are administered once daily.158. The method of embodiment 156, wherein one or more of the singletablets or pharmaceutical compositions are administered twice daily.159. The method of embodiment 156, wherein two tablets are administeredonce daily.160. The method according to any one of embodiments 156-159, whereinsaid patient has cystic fibrosis is chosen from patients withF508del/minimal function genotypes, patients with F508del/F508delgenotypes, patients with F508del/gating genotypes, and patients withF508del/residual function genotypes.161. The method of embodiment 160, wherein the patient with aF508del/minimal function genotype has a minimal function mutation chosenfrom:

Mutation S4X C276X G542X R792X E1104X G27X Q290X G550X E822X R1158X Q39XG330X Q552X W846X R1162X W57X W401X R553X Y849X S1196X E60X Q414X E585XR851X W1204X R75X S434X G673X Q890X L1254X E92X S466X Q685X S912X S1255XQ98X S489X R709X Y913X W1282X Y122X Q493X K710X W1089X Q1313X E193XW496X L732X Y1092X E1371X L218X C524X R764X W1098X Q1382X Q220X Q525XR785X R1102X Q1411X 185 + 1G→T 711 + 5G→A 1717 − 8G→A 2622 + 1G→A 3121 −1G→A 296 + 1G→A 712 − 1G→T 1717 − 1G→A 2790 − 1G→C 3500 − 2A→G 405 +1G→A 1248 + 1G→A 1811 + 1G→C 3040G→C 3600 + 2insT 405 + 3A→C 1249 − 1G→A1811 + 1.6kbA→G (G970R) 3850 − 1G→A 406 − 1G→A 1341 + 1G→A 1812 − 1G→A3120G→A 4005 + 1G→A 621 + 1G→T 1525 − 2A→G 1898 + 1G→A 3120 + 1G→A4374 + 1G→T 711 + 1G→T 1525 − 1G→A 1898 + 1G→C 3121 − 2A→G 182delT1119delA 1782delA 2732insA 3876delA 306insA 1138insG 1824delA 2869insG3878delG 365-366insT 1154insTC 2043delG 2896insAG 3905insT 394delTT1161delC 2143delT 2942insT 4016insT 442delA 1213delT 2183AA→G^(a)2957delT 4021dupT 444delA 1259insA 2184delA 3007delG 4040delA 457TAT→G1288insTA 2184insA 3028delA 4279insA 541delC 1471delA 2307insA 3171delC4326delTC 574delA 1497delGG 2347delG 3659delC 663delT 1548delG 2585delT3737delA 935delA 1609delCA 2594delGT 3791delC 1078delT 1677delTA2711delT 3821delT CFTRdele2,3 1461ins4 2991del32 CFTRdele22,23 1924del73199del6^(a) 124del23bp 2055del9→A 3667ins4 852del222105-2117del13insAGAAA 4010del4 991del5 2721del11 4209TGTT→AA A46D^(b)V520F Y569D^(b) N1303K G85E A559T^(b) L1065P R347P R560T R1066CL467P^(b) R560S L1077P^(b) I507del A561E M1101K162. The method of embodiment 160, wherein the patient with aF508del/gating genotype has a gating mutation chosen from G178R, S549N,S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.163. The method of embodiment 160, wherein the patient with aF508del/residual function genotype has a residual function mutationchosen from 2789+5G→A, 3849+10kbC→T, 3272-26A→G, 711+3A→G, E56K, P67L,R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X,S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, K1060T,R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C,D614G, G1069R, R1162L, E56K, A1067T, E193K, and K1060T.164. A method of preparing a single tablet of any one of embodiments 1,41, 59, 61, 71, 110, 127, 129, or 155, comprising

(a) mixing Compound I and the first and second solid dispersions to forma first mixture; and

(b) compressing a tablet mixture comprising the first mixture into atablet.

165. The method of embodiment 164, wherein the tablet mixture furthercomprises one or more pharmaceutically acceptable excipients, and themethod further comprises mixing the first mixture with said one or moreexcipients to form the tablet mixture.166. The method of embodiment 164 or 165, further comprising coating thetablet.167. A method of preparing a single tablet of embodiment 61 or 129,comprising

(a) mixing Compound I and the first and second solid dispersions to forma first mixture;

(b) mixing the first mixture with said microcrystalline cellulose,croscarmellose sodium and magnesium stearate to form a tablet mixture;and (c) compressing the tablet mixture into a tablet.

168. The method of embodiment 167, further comprising coating thetablet.

Additional exemplary embodiments of the disclosure include:

1. A pharmaceutical composition comprising

(a) 25 mg to 250 mg of Compound I:

(b) a first solid dispersion comprising 20 mg to 150 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 25 mg to 200 mg of CompoundIII-d:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.2. The pharmaceutical composition of embodiment 1, wherein at least oneof the first or second solid dispersions is a spray-dried dispersion.3. The pharmaceutical composition of embodiment 1, wherein both of thefirst and second solid dispersions are spray-dried dispersions.4. The pharmaceutical composition of embodiment 1, wherein said polymerin the first solid dispersion is hydroxypropyl methylcellulose; and saidpolymer in the second solid dispersion is hydroxypropyl methylcelluloseacetate succinate.5. The pharmaceutical composition of embodiment 1, wherein said polymerin the first solid dispersion is HPMC E15; and said polymer in thesecond solid dispersion is hydroxypropyl methylcellulose acetatesuccinate H.6. The pharmaceutical composition of embodiment 1, wherein said polymerin the first solid dispersion is HPMC E15; and said polymer in thesecond solid dispersion is hydroxypropyl methylcellulose acetatesuccinate HG.7. The pharmaceutical composition of any one of embodiments 1-6,comprising 25 mg to 75 mg or 80 mg to 120 mg of Compound I.8. The pharmaceutical composition of any one of embodiments 1-6,comprising 80 mg to 120 mg, 85 mg to 115 mg, 90 mg to 110 mg, or 95 mgto 105 mg of Compound I.9. The pharmaceutical composition of any one of embodiments 1-6,comprising 25 mg, 50 mg, or 100 mg of Compound I.10. The pharmaceutical composition of any one of embodiments 1-6,comprising 75 mg to 125 mg of Compound I.11. The pharmaceutical composition of any one of embodiments 1-10,wherein the first solid dispersion comprises 25 mg to 75 mg of CompoundII.12. The pharmaceutical composition of any one of embodiments 1-10,wherein the first solid dispersion comprises 50 mg of Compound II.13. The pharmaceutical composition of any one of embodiments 1-12,wherein the second solid dispersion comprises 25 mg to 50 mg, 25 mg to75 mg, 50 mg to 100 mg, 75 mg to 125 mg, or 125 mg to 175 mg of CompoundIII-d.14. The pharmaceutical composition of any one of embodiments 1-12,wherein the second solid dispersion comprises 75 mg or 150 mg ofCompound III-d.15. The pharmaceutical composition of any one of embodiments 1-6,comprising50 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg to 75 mg of Compound II; andthe second solid dispersion comprises 75 mg to 125 mg of Compound III-d.16. The pharmaceutical composition of any one of embodiments 1-6,comprising(a) 75 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III-d; or (b)100 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III-d.17. The pharmaceutical composition of any one of embodiments 1-17,wherein the second solid dispersion further comprises 0.5% sodium laurylsulfate relative to the total weight of the second solid dispersion.18. The pharmaceutical composition of any one of embodiments 1-18,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.19. The pharmaceutical composition of embodiment 19, wherein:

fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose monohydrate, dicalcium phosphate,mannitol, copovidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, starch,Maltodextrin, agar, and guar gum;

disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose;

lubricants are chosen from magnesium stearate, sodium stearyl fumarate,calcium stearate, sodium stearate, stearic acid, and talc; and

glidants are colloidal silicon dioxide.

20. The pharmaceutical composition of any one of embodiments 1-19,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III-d are independently substantially amorphous.21. The pharmaceutical composition of any one of embodiments 1-20,wherein the pharmaceutical composition is a tablet or in the form ofgranules.22. The pharmaceutical composition of embodiment 1, further comprisingmicrocrystalline cellulose; croscarmellose sodium; and optionallymagnesium stearate.23. The pharmaceutical composition of embodiment 22, wherein thepharmaceutical composition comprises 50 mg to 250 mg of microcrystallinecellulose; 10 mg to 45 mg of croscarmellose sodium; and optionally 1 mgto 10 mg of magnesium stearate.24. The pharmaceutical composition of any one of embodiments 1-23,wherein the weight ratio of Compound I in (a):Compound II in(b):Compound III-d in (c) is 4:2:3, 2:2:3, or 1:2:3.25. A pharmaceutical composition comprising:

(a) 10 wt % to 30 wt % of Compound I:

relative to the total weight of the pharmaceutical composition;(b) 10 wt % to 30 wt % of a first solid dispersion relative to the totalweight of the pharmaceutical composition,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) 10 wt % to 30 wt % of a second solid dispersion relative to thetotal weight of the pharmaceutical composition;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.26. The pharmaceutical composition of embodiment 25, wherein at leastone of the first or second solid dispersions is a spray-drieddispersion.27. The pharmaceutical composition of embodiment 25, wherein both of thefirst and second solid dispersions are spray-dried dispersions.28. The pharmaceutical composition of embodiment 25, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.29. The pharmaceutical composition of embodiment 25, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.30. The pharmaceutical composition of embodiment 25, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of CompoundIII-d relative to the total weight of the second solid dispersion, 0.5%sodium lauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.31. The pharmaceutical composition of any one of embodiments 25-30,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.32. The pharmaceutical composition of any one of embodiments 25-31,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.33. The pharmaceutical composition of any one of embodiments 25-32,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III-d relative to the total weight of the second soliddispersion.34. The pharmaceutical composition of any one of embodiments 25-33,wherein the second solid dispersion comprises 80 wt % of Compound III-drelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.35. The pharmaceutical composition of any one of embodiments 25-34,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.36. The pharmaceutical composition of embodiment 35, wherein:

fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose monohydrate, dicalcium phosphate,mannitol, copovidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, starch,Maltodextrin, agar, and guar gum;

disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose;

lubricants are chosen from magnesium stearate, sodium stearyl fumarate,calcium stearate, sodium stearate, stearic acid, and talc; and

glidants are colloidal silicon dioxide.

37. The pharmaceutical composition of any one of embodiments 25-36,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III-d is independently substantially amorphous.38. The pharmaceutical composition of any one of embodiments 25-37,wherein the pharmaceutical composition is a tablet or in the form ofgranules.39. The pharmaceutical composition of embodiment 35, further comprisingmicrocrystalline cellulose; croscarmellose sodium; and magnesiumstearate.40. The pharmaceutical composition of embodiment 39, wherein thepharmaceutical composition comprises 50 mg to 250 mg of microcrystallinecellulose; 10 mg to 45 mg of croscarmellose sodium; and optionally 1 mgto 10 mg of magnesium stearate.41. The pharmaceutical composition of embodiment 39, wherein thepharmaceutical composition comprises 15 wt % to 45 wt % ofmicrocrystalline cellulose relative to the total weight of thepharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodium;and optionally 0.5 wt % to 3 wt % mg of magnesium stearate.42. The pharmaceutical composition of any one of embodiments 25-41,wherein the weight ratio of Compound I in (a):Compound II in(b):Compound III-d in (c) is 4:2:3, 2:2:3 or 1:2:3.43. A pharmaceutical composition comprising:

(a) Compound I:

(b) a first solid dispersion,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer; and(c) a second solid dispersion;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer, whereinthe weight ratio of Compound I in (a):Compound II in (b):Compound III-din (c) ranges from 1-4:2:3.44. The pharmaceutical composition of embodiment 43, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.45. The pharmaceutical composition of embodiment 43, wherein both of thefirst and second solid dispersions are spray-dried dispersions.46. The pharmaceutical composition of embodiment 43, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.47. The pharmaceutical composition of embodiment 43, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.48. The pharmaceutical composition of embodiment 43, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of CompoundIII-d relative to the total weight of the second solid dispersion, 0.5%sodium lauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.49. The pharmaceutical composition of any one of embodiments 43-48,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.50. The pharmaceutical composition of any one of embodiments 43-49,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.51. The pharmaceutical composition of any one of embodiments 43-50,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III-d relative to the total weight of the second soliddispersion.52. The pharmaceutical composition of any one of embodiments 43-51,wherein the second solid dispersion comprises 80 wt % of Compound III-drelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.53. The pharmaceutical composition of any one of embodiments 43-52,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.54. The pharmaceutical composition of embodiment 53, wherein:

fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose monohydrate, dicalcium phosphate,mannitol, copovidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, starch,Maltodextrin, agar, and guar gum;

disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose;

lubricants are chosen from magnesium stearate, sodium stearyl fumarate,calcium stearate, sodium stearate, stearic acid, and talc; and

glidants are colloidal silicon dioxide.

55. The pharmaceutical composition of any one of embodiments 43-54,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III-d is independently substantially amorphous.56. The pharmaceutical composition of any one of embodiments 43-55,wherein the pharmaceutical composition is a tablet or in the form ofgranules.57. The pharmaceutical composition of any one of embodiments 43-56,wherein the weight ratio of Compound I in (a):Compound II in(b):Compound III-d in (c) is 4:2:3, 2:2:3 or 1:2:3.58. The pharmaceutical composition of embodiment 43, further comprisingmicrocrystalline cellulose; croscarmellose sodium; and magnesiumstearate.59. The pharmaceutical composition of embodiment 58, wherein thepharmaceutical composition comprises 50 mg to 250 mg of microcrystallinecellulose; 10 mg to 45 mg of croscarmellose sodium; and optionally 1 mgto 10 mg of magnesium stearate.60. The pharmaceutical composition of embodiment 58, wherein thepharmaceutical composition comprises 15 wt % to 45 wt % ofmicrocrystalline cellulose relative to the total weight of thepharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodium;and optionally 0.5 wt % to 3 wt % mg of magnesium stearate.61. A single tablet comprising:

(a) 25 mg to 125 mg of Compound I:

(b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt %Compound II relative to the total weight of the first solid dispersion:

and 20 wt % of a hydroxypropyl methylcellulose relative to the totalweight of the first solid dispersion; and(c) 90 mg to 95 mg of a second solid dispersion comprising 80 wt % ofCompound III-d relative to the total weight of the second soliddispersion:

0.5 wt % of sodium lauryl sulfate relative to the total weight of thesecond solid dispersion; and 19.5 wt % of a hydroxypropylmethylcellulose acetate succinate to the total weight of the secondsolid dispersion(d) 75 mg to 230 mg of microcrystalline cellulose;(e) 20 mg to 45 mg of croscarmellose sodium; and(f) 2 mg to 7 mg of magnesium stearate.62. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg or 35 mg to 75 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 190 mg to 205 mg of said microcrystalline cellulose;(e) 25 mg to 35 mg of said croscarmellose sodium; and(f) 3 mg to 7 mg of magnesium stearate.63. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.64. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 200 mg of said microcrystalline cellulose; and(f) 3 mg to 7 mg of magnesium stearate.65. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.66. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.67. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 35 mg to 40 mg of said croscarmellose sodium;(e) 105 mg to 115 mg of lactose monohydrate;(f) 220 mg to 230 mg of said microcrystalline cellulose;(g) 1 mg to 5 mg of colloidal silicon dioxide; and(h) 4 mg to 7 mg of magnesium stearate.68. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 40 mg to 50 mg of lactose monohydrate;(f) 90 mg to 100 mg of said microcrystalline cellulose;(g) 1 mg to 5 mg of colloidal silicon dioxide; and(h) 2 mg to 7 mg of magnesium stearate.69. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose;(f) 1 mg to 5 mg of colloidal silicon dioxide; and(g) 2 mg to 7 mg of magnesium stearate.70. The single tablet of embodiment 61, comprising:

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 30 mg of said croscarmellose sodium;(e) 135 mg to 145 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.71. A pharmaceutical composition comprising

(a) 15 mg to 250 mg of Compound I:

(b) a first solid dispersion comprising 10 mg to 150 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 25 mg to 200 mg of CompoundIII:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.72. The pharmaceutical composition of embodiment 71, wherein at leastone of the first or second solid dispersions is a spray-drieddispersion.73. The pharmaceutical composition of embodiment 71, wherein both of thefirst and second solid dispersions are spray-dried dispersions.74. The pharmaceutical composition of embodiment 71, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.75. The pharmaceutical composition of embodiment 71, wherein saidpolymer in the first solid dispersion is HPMC E15; and said polymer inthe second solid dispersion is hydroxypropyl methylcellulose acetatesuccinate H.76. The pharmaceutical composition of embodiment 71, wherein saidpolymer in the first solid dispersion is HPMC E15; and said polymer inthe second solid dispersion is hydroxypropyl methylcellulose acetatesuccinate HG.77. The pharmaceutical composition of any one of embodiments 71-76,comprising 25 mg to 75 mg or 80 mg to 120 mg of Compound I.78. The pharmaceutical composition of any one of embodiments 71-76,comprising 80 mg to 120 mg, 85 mg to 115 mg, 90 mg to 110 mg, or 95 mgto 105 mg of Compound I.79. The pharmaceutical composition of any one of embodiments 71-76,comprising 25 mg, 50 mg, or 100 mg of Compound I.80. The pharmaceutical composition of any one of embodiments 71-76,comprising 75 mg to 125 mg of Compound I.81. The pharmaceutical composition of any one of embodiments 71-80,wherein the first solid dispersion comprises 25 mg to 75 mg of CompoundII.82. The pharmaceutical composition of any one of embodiments 71-80,wherein the first solid dispersion comprises 50 mg of Compound II.83. The pharmaceutical composition of any one of embodiments 71-82,wherein the second solid dispersion comprises 25 mg to 50 mg, 25 mg to75 mg, 50 mg to 100 mg, 75 mg to 125 mg, or 125 mg to 175 mg of CompoundIII.84. The pharmaceutical composition of any one of embodiments 71-82,wherein the second solid dispersion comprises 75 mg of Compound III.85. The pharmaceutical composition of any one of embodiments 71-76,comprising(a) 50 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg to 75 mg of Compound II; andthe second solid dispersion comprises 50 mg to 175 mg of Compound III;or(b) 70 mg to 240 mg of Compound I; and whereinthe first solid dispersion comprises 30 mg to 120 mg of Compound II; andthe second solid dispersion comprises 50 mg to 170 mg of Compound III;or(c) 30 mg to 120 mg of Compound I; and whereinthe first solid dispersion comprises 15 mg to 60 mg of Compound II; andthe second solid dispersion comprises 20 mg to 90 mg of Compound III; or(d) 30 mg to 120 mg of Compound I; and whereinthe first solid dispersion comprises 15 mg to 60 mg of Compound II; andthe second solid dispersion comprises 50 mg to 170 mg of Compound III;or(e) 15 mg to 55 mg of Compound I; and whereinthe first solid dispersion comprises 10 mg to 50 mg of Compound II; andthe second solid dispersion comprises 20 mg to 90 mg of Compound III.86. The pharmaceutical composition of any one of embodiments 71-76,comprising(a) 75 mg to 125 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III; or(b) 100 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III; or(c) 200 mg of Compound I; and whereinthe first solid dispersion comprises 100 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(d) 100 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(e) 50 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III; or(f) 100 mg of Compound I; and whereinthe first solid dispersion comprises 100 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(g) 50 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III; or(h) 50 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(i) 25 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(j) 25 mg of Compound I; and whereinthe first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 150 mg of Compound III; or(k) 12.5 mg of Compound I; and whereinthe first solid dispersion comprises 25 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III; or(l) 30 mg to 70 mg of Compound I; and whereinthe first solid dispersion comprises 15 mg to 40 mg of Compound II; andthe second solid dispersion comprises 20 mg to 55 mg of Compound III; or(m) 70 mg to 130 mg of Compound I; and whereinthe first solid dispersion comprises 30 mg to 70 mg of Compound II; andthe second solid dispersion comprises 50 mg to 100 mg of Compound III.87. The pharmaceutical composition of any one of embodiments 71-86,wherein the second solid dispersion further comprises 0.5% sodium laurylsulfate relative to the total weight of the second solid dispersion.88. The pharmaceutical composition of any one of embodiments 71-87,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, lubricants, andglidants.89. The pharmaceutical composition of embodiment 88, wherein:

said fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose monohydrate, dicalcium phosphate,mannitol, copovidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, starch,Maltodextrin, agar, and guar gum;

said disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose;

said lubricants are chosen from magnesium stearate, sodium stearylfumarate, calcium stearate, sodium stearate, stearic acid, and talc; and

said glidants are chosen from colloidal silicon dioxides.

90. The pharmaceutical composition any one of embodiments 71-89, whereinCompound I is substantially crystalline, and wherein each of CompoundsII and III are independently substantially amorphous.91. The pharmaceutical composition of embodiment 71, further comprisingmicrocrystalline cellulose; croscarmellose sodium; and optionallymagnesium stearate.92. The pharmaceutical composition of embodiment 91, wherein thepharmaceutical composition comprises 50 mg to 250 mg of microcrystallinecellulose; 10 mg to 45 mg of croscarmellose sodium; and optionally 1 mgto 10 mg of magnesium stearate.93. The pharmaceutical composition of any one of embodiments 71-92,wherein the pharmaceutical composition comprises 25 mg to 250 mg ofCompound I in (a): said first solid dispersion comprises 20 mg to 150 mgof Compound II in (b): and said second solid dispersion comprises 25 mgto 200 mg of Compound III.94. The pharmaceutical composition of any one of embodiments 1-23,wherein the weight ratio of Compound I in (a):Compound II in(b):Compound III in (c) is 4:2:3, 2:1:3, 2:2:3, 1:1:3, 1:2:3, or 1:2:6.95. A pharmaceutical composition comprising:

(a) 10 wt % to 30 wt % of Compound I:

relative to the total weight of the pharmaceutical composition;(b) 8 wt % to 30 wt % of a first solid dispersion relative to the totalweight of the pharmaceutical composition,wherein the first solid dispersion comprises 70 wt % to 90 wt % ofCompound II relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) 10 wt % to 45 wt % of a second solid dispersion relative to thetotal weight of the pharmaceutical composition;wherein the second solid dispersion comprises 70 wt % to 90 wt % ofCompound III relative to the total weight of the second soliddispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.96. The pharmaceutical composition of embodiment 95, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.97. The pharmaceutical composition of embodiment 95, wherein both of thefirst and second solid dispersions are spray-dried dispersions.98. The pharmaceutical composition of embodiment 95, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.99. The pharmaceutical composition of embodiment 95, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.100. The pharmaceutical composition of embodiment 95, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of Compound IIIrelative to the total weight of the second solid dispersion, 0.5% sodiumlauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.101. The pharmaceutical composition of any one of embodiments 95-100,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.102. The pharmaceutical composition of any one of embodiments 95-100,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.103. The pharmaceutical composition of any one of embodiments 95-102,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III relative to the total weight of the second soliddispersion.104. The pharmaceutical composition of any one of embodiments 95-103,wherein the second solid dispersion comprises 80 wt % of Compound IIIrelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.105. The pharmaceutical composition of any one of embodiments 95-104,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, and lubricants.106. The pharmaceutical composition of embodiment 105, wherein:

said fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose, dicalcium phosphate, mannitol,copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guargum;

said disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose; and

said lubricants are chosen from magnesium stearate, sodium stearylfumarate, calcium stearate, sodium stearate, stearic acid, and talc.

107. The pharmaceutical composition of any one of embodiments 95-107,wherein the pharmaceutical composition is a tablet or in the form ofgranules.108. The pharmaceutical composition of embodiment 95, further comprisingmicrocrystalline cellulose; croscarmellose sodium; and optionallymagnesium stearate.109. The pharmaceutical composition of embodiment 108, wherein thepharmaceutical composition comprises 15 wt % to 45 wt % ofmicrocrystalline cellulose relative to the total weight of thepharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodium;and optionally 0.5 wt % to 3 wt % mg of magnesium stearate.110. The pharmaceutical composition of any one of embodiments 95-109,wherein the pharmaceutical composition comprises 10 wt % to 30 wt % ofCompound I in (a): 8 wt % to 30 wt % of said first solid dispersion in(b): and 10 wt % to 30 wt % of said second solid dispersion in (c).111. The pharmaceutical composition of any one of embodiments 95-110,wherein the weight ratio of Compound I in (a):Compound II in(b):Compound III in (c) is 4:2:3. 2:1:3, 2:2:3, 1:1:3, 1:2:3, or 1:2:6.112. A pharmaceutical composition comprising:

(a) Compound I:

(b) a first solid dispersion comprising 70 wt % to 90 wt % of CompoundII relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and(c) a second solid dispersion comprising 70 wt % to 90 wt % of CompoundIII relative to the total weight of the second solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion, whereinthe weight ratio of Compound I in (a):Compound II in (b):Compound III in(c) in a range of 4:2:3-6.113. The pharmaceutical composition of embodiment 112, wherein at leastone of the second or third solid dispersions is a spray-drieddispersion.114. The pharmaceutical composition of embodiment 112, wherein both ofthe first and second solid dispersions are spray-dried dispersions.115. The pharmaceutical composition of embodiment 112, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose;and said polymer in the second solid dispersion is hydroxypropylmethylcellulose acetate succinate.116. The pharmaceutical composition of embodiment 112, wherein saidpolymer in the first solid dispersion is hydroxypropyl methylcellulose(HPMC E15); and said polymer in the second solid dispersion ishydroxypropyl methylcellulose acetate succinate H.117. The pharmaceutical composition of embodiment 112, wherein:the first solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; andthe second solid dispersion comprises 70 wt % to 85 wt % of Compound IIIrelative to the total weight of the second solid dispersion, 0.5% sodiumlauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.118. The pharmaceutical composition of any one of embodiments 112-117,wherein the first solid dispersion comprises 75 wt % to 85 wt % ofCompound II relative to the total weight of the first solid dispersion.119. The pharmaceutical composition of any one of embodiments 112-117,wherein the first solid dispersion comprises 80 wt % of Compound IIrelative to the total weight of the first solid dispersion; and 20 wt %of hydroxypropyl methylcellulose relative to the total weight of thefirst solid dispersion.120. The pharmaceutical composition of any one of embodiments 112-119,wherein the second solid dispersion comprises 75 wt % to 85 wt % ofCompound III relative to the total weight of the second soliddispersion.121. The pharmaceutical composition of any one of embodiments 112-120,wherein the second solid dispersion comprises 80 wt % of Compound IIIrelative to the total weight of the second solid dispersion; 0.5% ofsodium lauryl sulfate relative to the total weight of the second soliddispersion, and 19.5 wt % of hydroxypropyl methylcellulose acetatesuccinate relative to the total weight of the second solid dispersion.122. The pharmaceutical composition of any one of embodiments 112-121,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, and lubricants.123. The pharmaceutical composition of embodiment 122, wherein:

said fillers are chosen from microcrystalline cellulose, silicifiedmicrocrystalline cellulose, lactose, dicalcium phosphate, mannitol,copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methyl cellulose, ethyl cellulose, starch, Maltodextrin, agar, and guargum;

said disintegrants are chosen from croscarmellose sodium, sodium starchglycolate, crospovidone, corn or pre-gelatinized starch, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, andmicrocrystalline cellulose; and

said lubricants are chosen from magnesium stearate, sodium stearylfumarate, calcium stearate, sodium stearate, stearic acid, and talc.

124. The pharmaceutical composition of any one of embodiments 112-123,wherein Compound I is substantially crystalline, and wherein each ofCompounds II and III is independently substantially amorphous.125. The pharmaceutical composition of any one of embodiments 112-124,wherein the pharmaceutical composition is a tablet or in the form ofgranules.126. The pharmaceutical composition of embodiment 112, furthercomprising microcrystalline cellulose; croscarmellose sodium; andmagnesium stearate.127. The pharmaceutical composition of embodiment 58, wherein thepharmaceutical composition comprises 15 wt % to 45 wt % ofmicrocrystalline cellulose relative to the total weight of thepharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodium;and 0.5 wt % to 3 wt % mg of magnesium stearate.128. The pharmaceutical composition of embodiment 58, wherein the weightratio of Compound I in (a):Compound II in (b):Compound III in (c) in4:2:3, 2:1:3, 2:2:3, 1:1:3, 1:2:3, or 1:2:6.129. A single tablet comprising:

(a) 25 mg to 125 mg of Compound I:

(b) 60 mg to 65 mg of a first solid dispersion comprising 80 wt %Compound II relative to the total weight of the first solid dispersion:

and 20 wt % of a hydroxypropyl methylcellulose relative to the totalweight of the first solid dispersion; and(c) 90 mg to 95 mg, or 180 mg to 190 mg of a second solid dispersioncomprising 80 wt % of Compound III relative to the total weight of thesecond solid dispersion:

0.5 wt % of sodium lauryl sulfate relative to the total weight of thesecond solid dispersion; and 19.5 wt % of a hydroxypropylmethylcellulose acetate succinate to the total weight of the secondsolid dispersion(d) 85 mg to 275 mg of microcrystalline cellulose;(e) 10 mg to 35 mg of croscarmellose sodium; and(f) 2 mg to 7 mg of magnesium stearate.130. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.131. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.132. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 200 mg to 210 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.133. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.134. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 270 mg to 275 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.135. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.136. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.137. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 12 mg to 17 mg of said croscarmellose sodium;(e) 160 mg to 170 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.138. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 180 mg to 190 mg of said second solid dispersion;(d) 10 mg to 20 mg of said croscarmellose sodium;(e) 260 mg to 270 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.139. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.140. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 200 mg to 210 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.141. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 85 mg to 95 mg of said microcrystalline cellulose; and(f) 2 mg to 6 mg of magnesium stearate.142. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 20 mg to 25 mg of said croscarmellose sodium;(e) 270 mg to 275 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.143. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.144. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 205 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.145. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 25 mg to 35 mg of said croscarmellose sodium;(e) 195 mg to 200 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.146. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 12 mg to 17 mg of said croscarmellose sodium;(e) 160 mg to 170 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.147. The single tablet of embodiment 129, comprising

(a) 90 mg to 110 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 90 mg to 95 mg of said second solid dispersion;(d) 10 mg to 20 mg of said croscarmellose sodium;(e) 260 mg to 270 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.148. A single tablet comprising:

(a) 10 mg to 110 mg of Compound I:

(b) 25 mg to 70 mg of a first solid dispersion comprising 80 wt %Compound II relative to the total weight of the first solid dispersion:

and 20 wt % of a hydroxypropyl methylcellulose relative to the totalweight of the first solid dispersion; and(c) 85 mg to 195 mg, of a second solid dispersion comprising 80 wt % ofCompound III relative to the total weight of the second soliddispersion:

0.5 wt % of sodium lauryl sulfate relative to the total weight of thesecond solid dispersion; and 19.5 wt % of a hydroxypropylmethylcellulose acetate succinate to the total weight of the secondsolid dispersion(d) 10 mg to 45 mg of croscarmellose sodium; and(e) 95 mg to 280 mg of microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.149. The single tablet of embodiment 148, comprising

(a) 95 mg to 105 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 185 mg to 190 mg of said second solid dispersion;(d) 35 mg to 45 mg of said croscarmellose sodium;(e) 260 mg to 280 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.150. The single tablet of embodiment 148, comprising

(a) 45 mg to 55 mg of Compound I;

(b) 25 mg to 55 mg of said first solid dispersion;(c) 90 mg to 100 mg of said second solid dispersion;(d) 15 mg to 25 mg of said croscarmellose sodium;(e) 125 mg to 145 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.151. The single tablet of embodiment 148, comprising

(a) 45 mg to 55 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 185 mg to 190 mg of said second solid dispersion;(d) 30 mg to 40 mg of said croscarmellose sodium;(e) 220 mg to 245 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.152. The single tablet of embodiment 148, comprising

(a) 20 mg to 30 mg of Compound I;

(b) 30 mg to 35 mg of said first solid dispersion;(c) 90 mg to 100 mg of said second solid dispersion;(d) 15 mg to 25 mg of said croscarmellose sodium;(e) 110 mg to 120 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.153. The single tablet of embodiment 148, comprising

(a) 20 mg to 30 mg of Compound I;

(b) 60 mg to 65 mg of said first solid dispersion;(c) 185 mg to 190 mg of said second solid dispersion;(d) 35 mg to 45 mg of said croscarmellose sodium;(e) 200 mg to 220 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.154. The single tablet of embodiment 148, comprising

(a) 10 mg to 15 mg of Compound I;

(b) 25 mg to 35 mg of said first solid dispersion;(c) 90 mg to 100 mg of said second solid dispersion;(d) 10 mg to 20 mg of said croscarmellose sodium;(e) 100 mg to 115 mg of said microcrystalline cellulose; and(f) 2 mg to 7 mg of magnesium stearate.155. A pharmaceutical composition comprising(a) 12 wt % to 30 wt % Compound I relative to the total weight of thepharmaceutical composition:

(b) 10 wt % to 15 wt % of Compound II relative to the total weight ofthe pharmaceutical composition:

(c) 10 wt % to 25 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition:

(d) 20 wt % to 45 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-8 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 2 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.156. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 18% to 23 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 8 wt % to 12 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 13 wt % to 18 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 35 wt % to 45 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.157. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 15% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 5 wt % to 10 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 7 wt % to 15 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 30 wt % to 50 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.158. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 20% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 15 wt % to 20 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 15 wt % to 25 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.159. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 20% to 25 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 15 wt % to 20 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 25 wt % to 35 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.160. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 22% to 28 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 10 wt % to 15 wt % of Compound II relative to the total weight ofthe pharmaceutical composition;(c) 15 wt % to 25 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 15 wt % to 25 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-7 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.161. The pharmaceutical composition of embodiment 155, wherein thepharmaceutical composition comprises:(a) 15% to 20 wt % Compound I relative to the total weight of thepharmaceutical composition;(b) 7 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition;(c) 10 wt % to 15 wt % of Compound III or Compound III-d relative to thetotal weight of the pharmaceutical composition;(d) 45 wt % to 55 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 3 wt %-5 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 1.5 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.162. A pharmaceutical composition comprising(a) 12 wt % to 30 wt % Compound I relative to the total weight of thepharmaceutical composition:

(b) 5 wt % to 15 wt % of Compound II relative to the total weight of thepharmaceutical composition:

(c) 15 wt % to 35 wt % of Compound III relative to the total weight ofthe pharmaceutical composition:

(d) 15 wt % to 45 wt % of microcrystalline cellulose relative to thetotal weight of the pharmaceutical composition;(e) 1 wt %-10 wt % of croscarmellose sodium relative to the total weightof the pharmaceutical composition; and(f) 0.5 wt % to 3 wt % of magnesium stearate relative to the totalweight of the pharmaceutical composition.163. The pharmaceutical composition of any one of embodiments 155-162,wherein the pharmaceutical composition is a tablet.164. The pharmaceutical composition or single tablet of any one ofembodiments 1-163, wherein Compound I is Crystalline Form A.165. The pharmaceutical composition or single tablet of embodiment 164,wherein Compound I Crystalline Form A is in substantially pure form.166. The pharmaceutical composition or single tablet of embodiment 164,wherein Compound I Crystalline Form A is characterized by an X-raypowder diffractogram having a signal at at least three two-theta valueschosen from 6.6±0.2, 7.6±0.2, 9.6±0.2, 12.4±0.2, 13.1±0.2, 15.2±0.2,16.4±0.2, 18.2±0.2, and 18.6±0.2.167. A method of treating cystic fibrosis in a patient comprising orallyadministering to the patient one or more of the single tablet orpharmaceutical composition of any one of embodiments 1-163.168. The method of embodiment 167, wherein one or more of the singletablets or pharmaceutical compositions are administered once daily ortwice daily.169. The method of embodiment 168, wherein two tablets are administeredonce daily.170. The method according to any one of embodiments 167-168, whereinsaid patient has cystic fibrosis is chosen from patients withF508del/minimal function genotypes, patients with F508del/F508delgenotypes, patients with F508del/gating genotypes, and patients withF508del/residual function genotypes.171. The method of embodiment 170, wherein the patient with aF508del/minimal function genotype has a minimal function mutation chosenfrom:

Mutation Q2X L218X Q525X R792X E1104X S4X Q220X G542X E822X W1145X W19XY275X G550X W882X R1158X G27X C276X Q552X W846X R1162X Q39X Q290X R553XY849X S1196X W57X G330X E585X R851X W1204X E60X W401X G673X Q890X L1254XR75X Q414X Q685X S912X S1255X L88X S434X R709X Y913X W1282X E92X S466XK710X Q1042X Q1313X Q98X S489X Q715X W1089X Q1330X Y122X Q493X L732XY1092X E1371X E193X W496X R764X W1098X Q1382X W216X C524X R785X R1102XQ1411X 185 + 1G→T 711 + 5G→A 1717 − 8G→A 2622 + 1G→A 3121 − 1G→A 296 +1G→A 712 − 1G→T 1717 − 1G→A 2790 − 1G→C 3500 − 2A→G 296 + 1G→T 1248 +1G→A 1811 + 1G→C 3040G→C 3600 + 2insT 405 + 1G→A 1249 − 1G→A 1811 +1.6kbA→G (G970R) 3850 − 1G→A 405 + 3A→C 1341 + 1G→A 1811 + 1643G→T3120G→A 4005 + 1G→A 406 − 1G→A 1525 − 2A→G 1812 − 1G→A 3120 + 1G→A4374 + 1G→T 621 + 1G→T 1525 − 1G→A 1898 + 1G→A 3121-2A→G 711 + 1G→T1898 + 1G→C 182delT 1078delT 1677delTA 2711delT 3737delA 306insA1119delA 1782delA 2732insA 3791delC 306delTAGA 1138insG 1824delA2869insG 3821delT 365-366insT 1154insTC 1833delT 2896insAG 3876delA394delTT 1161delC 2043delG 2942insT 3878delG 442delA 1213delT 2143delT2957delT 3905insT 444delA 1259insA 2183AA→G^(a) 3007delG 4016insT457TAT→G 1288insTA 2184delA 3028delA 4021dupT 541delC 1343delG 2184insA3171delC 4022insT 574delA 1471delA 2307insA 3171insC 4040delA 663delT1497delGG 2347delG 3271delGG 4279insA 849delG 1548delG 2585delT 3349insT4326delTC 935delA 1609del CA 2594delGT 3659delC CFTRdele1 CFTRdele16-17b1461ins4 CFTRdele2 CFTRdele17a,17b 1924del7 CFTRdele2,3 CFTRdele17a-182055del9→A CFTRdele2-4 CFTRdele19 2105-2117del13insAGAAACFTRdele3-10,14b-16 CFTRdele19-21 2372del8 CFTRdele4-7 CFTRdele212721del11 CFTRdele4-11 CFTRdele22-24 2991del32 CFTR50kbdel CFTRdele22,233121-977_3499 + 248del2515 CFTRdup6b-10 124del23bp 3667ins4 CFTRdele11602del14 4010del4 CFTRdele13,14a 852del22 4209TGTT→AA CFTRdele14b-17b991del5 A46D^(b) V520F Y569D^(b) N1303K G85E A559T^(b) L1065P R347PR560T R1066C L467P^(b) R560S L1077P^(b) I507del A561E M1101K ^(a)Alsoknown as 2183delAA→G.172. The method of embodiment 170, wherein the patient with aF508del/gating genotype has a gating mutation chosen from G178R, S549N,S549R, G551D, G551S, G1244E, S1251N, S1255P, and G1349D.173. The method of embodiment 170, wherein the patient with aF508del/residual function genotype has a residual function mutationchosen from 2789+5G→A, 3849+10kbC→T, 3272-26A→G, 711+3A→G, E56K, P67L,R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X,S945L, S977F, F1052V, R1070W, F1074L, D1152H, D1270N, E193K, K1060T,R117H, S1235R, I1027T, R668C, G576A, M470V, L997F, R75Q, R1070Q, R31C,D614G, G1069R, R1162L, E56K, A1067T, E193K, and K1060T.174. A method of preparing a single tablet of any one of embodiments 1,41, 59, 61, 71, 110, 127, 129, 148, or 163, comprising

(a) mixing Compound I and the first and second solid dispersions to forma first mixture; and

(b) compressing a tablet mixture comprising the first mixture into atablet.

175. The method of embodiment 174, wherein the tablet mixture furthercomprises one or more pharmaceutically acceptable excipients, and themethod further comprises mixing the first mixture with said one or moreexcipients to form the tablet mixture.176. The method of embodiment 173 or 174, further comprising coating thetablet.177. A method of preparing a single tablet of embodiment 61 or 129,comprising

(a) mixing Compound I and the first and second solid dispersions to forma first mixture;

(b) mixing the first mixture with said microcrystalline cellulose,croscarmellose sodium and magnesium stearate to form a tablet mixture;and (c) compressing the tablet mixture into a tablet.

178. The method of embodiment 177, further comprising coating thetablet.179. A pharmaceutical composition having the following formulation:

mg per Component tablet Intragranular Compound I 50 a solid dispersioncomprising: 31 80 wt % substantially amorphous Compound II, and 20 wt %HPMC a solid dispersion comprising: 47 80 wt % substantially amorphousCompound III, 19.5 wt % HPMCAS, and 0.5 wt % sodium lauryl sulfateCroscarmellose sodium 15 Microcrystaline cellulose 40 ExtragranularMicrocrystaline cellulose 59 Magnesium stearate 2 Total Core Tablet 244Film coat 7 Total 251180. The pharmaceutical composition of any of embodiments 1-60, 71-128,155-168, or179, wherein the pharmaceutical composition is a tablet.

Methods of Preparing Compounds and Tablets

General Experimental Procedures

Reagents and starting materials were obtained by commercial sourcesunless otherwise stated and were used without purification. Proton andcarbon NMR spectra were acquired on either of a Bruker Biospin DRX 400MHz FTNMR spectrometer operating at a ¹H and ¹³C resonant frequency of400 and 100 MHz respectively, or on a 300 MHz NMR spectrometer. Onedimensional proton and carbon spectra were acquired using a broadbandobserve (BBFO) probe with 20 Hz sample rotation at 0.1834 and 0.9083Hz/Pt digital resolution respectively. All proton and carbon spectrawere acquired with temperature control at 30° C. using standard,previously published pulse sequences and routine processing parameters.

Final purity of compounds was determined by reversed phase UPLC using anAcquity UPLC BEH C₁₈ column (50×2.1 mm, 1.7 μm particle) made by Waters(pn: 186002350), and a dual gradient run from 1-99% mobile phase B over3.0 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B=CH₃CN(0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C. Final purity was calculated by averaging thearea under the curve (AUC) of two UV traces (220 nm, 254 nm).Low-resolution mass spectra were reported as [M+H]⁺ species obtainedusing a single quadrupole mass spectrometer equipped with anelectrospray ionization (ESI) source capable of achieving a massaccuracy of 0.1 Da and a minimum resolution of 1000 (no units onresolution) across the detection range. Optical purity of methyl(2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gaschromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument,using a Restek Rt-βDEXcst (30 m×0.25 mm×0.25 um_df) column, with a 2.0mL/min flow rate (H₂ carrier gas), at an injection temperature of 220°C. and an oven temperature of 120° C., 15 minutes.

The powder x-ray diffraction measurements were performed usingPANalytical's X-pert Pro diffractometer at room temperature with copperradiation (1.54060 Å). The incident beam optic was comprised of avariable divergence slit to ensure a constant illuminated length on thesample and on the diffracted beam side; a fast linear solid statedetector was used with an active length of 2.12 degrees 2 theta measuredin a scanning mode. The powder sample was packed on the indented area ofa zero background silicon holder and spinning was performed to achievebetter statistics. A symmetrical scan was measured from 3-40 degrees 2theta with a step size of 0.017 degrees and a scan step time of 15.5s.

Solid state ¹³C and ¹⁹F NMR data was obtained using Bruker-Biospin 400MHz wide-bore spectrometer equipped with Bruker-Biospin 4 mm HFX probewas used. Samples were packed into 4 mm rotors and spun under MagicAngle Spinning (MAS) condition with typical spinning speed of 12.5 kHz.The proton relaxation time was estimated from ¹H MAS T₁ saturationrecovery relaxation experiment and used to set up proper recycle delayof the ¹³C cross-polarization (CP) MAS experiment. The fluorinerelaxation time was estimated from ¹⁹F MAS T₁ saturation recoveryrelaxation experiment and used to set up proper recycle delay of the ¹⁹FMAS experiment. The CP contact time of CPMAS experiments was set to 2ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed.All spectra were externally referenced by adjusting the magnetic fieldto set carbon resonance of adamantane to 29.5 ppm. TPPM15 protondecoupling sequence was used with the field strength of approximately100 kHz for both ¹³C and ¹⁹F acquisitions.

Final purity of compounds was determined by reversed phase UPLC using anAcquity UPLC BEH C₁₈ column (50×2.1 mm, 1.7 μm particle) made by Waters(pn: 186002350), and a dual gradient run from 1-99% mobile phase B over3.0 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B=CH₃CN(0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C. Final purity was calculated by averaging thearea under the curve (AUC) of two UV traces (220 nm, 254 nm).Low-resolution mass spectra were reported as [M+H]⁺ species obtainedusing a single quadrupole mass spectrometer equipped with anelectrospray ionization (ESI) source capable of achieving a massaccuracy of 0.1 Da and a minimum resolution of 1000 (no units onresolution) across the detection range. Optical purity of methyl(2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gaschromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument,using a Restek Rt-βDEXcst (30 m×0.25 mm×0.25 um_df) column, with a 2.0mL/min flow rate (H₂ carrier gas), at an injection temperature of 220°C. and an oven temperature of 120° C., 15 minutes.

Example 1. Synthesis of Compound I:N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound I)

Part A: Synthesis of (4S)-2,2,4-trimethylpyrrolidine Hydrochloride

Step 1: methyl-2,4-dimethyl-4-nitro-pentanoate

Tetrahydrofuran (THF, 4.5 L) was added to a 20 L glass reactor andstirred under N₂ at room temperature. 2-Nitropropane (1.5 kg, 16.83 mol)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.282 kg, 8.42 mol) werethen charged to the reactor, and the jacket temperature was increased to50° C. Once the reactor contents were close to 50° C., methylmethacrylate (1.854 kg, 18.52 mol) was added slowly over 100 minutes.The reaction temperature was maintained at or close to 50° C. for 21hours. The reaction mixture was concentrated in vacuo then transferredback to the reactor and diluted with methyl tert-butyl ether (MTBE) (14L). 2 M HCl (7.5 L) was added, and this mixture was stirred for 5minutes then allowed to settle. Two clear layers were visible—a loweryellow aqueous phase and an upper green organic phase. The aqueous layerwas removed, and the organic layer was stirred again with 2 M HCl (3 L).After separation, the HCl washes were recombined and stirred with MTBE(3 L) for 5 minutes. The aqueous layer was removed, and all of theorganic layers were combined in the reactor and stirred with water (3 L)for 5 minutes. After separation, the organic layers were concentrated invacuo to afford a cloudy green oil. Crude product was treated with MgSO₄and filtered to afford methyl-2,4-dimethyl-4-nitro-pentanoate as a cleargreen oil (3.16 kg, 99% yield).

¹H NMR (400 MHz, Chloroform-d) δ 3.68 (s, 3H), 2.56-2.35 (m, 2H),2.11-2.00 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H), 1.19 (d, J=6.8 Hz, 3H).

Step 2: Synthesis of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate

A reactor was charged with purified water (2090 L; 10 vol) and thenpotassium phosphate monobasic (27 kg, 198.4 moles; 13 g/L for watercharge). The pH of the reactor contents was adjusted to pH 6.5 (±0.2)with 20% (w/v) potassium carbonate solution. The reactor was chargedwith racemic methyl-2,4-dimethyl-4-nitro-pentanoate (209 kg; 1104.6moles), and Palatase 20000L lipase (13 L, 15.8 kg; 0.06 vol).

The reaction mixture was adjusted to 32±2° C. and stirred for 15-21hours, and pH 6.5 was maintained using a pH stat with the automaticaddition of 20% potassium carbonate solution. When the racemic startingmaterial was converted to >98% ee of the S-enantiomer, as determined bychiral GC, external heating was switched off. The reactor was thencharged with MTBE (35 L; 5 vol), and the aqueous layer was extractedwith MTBE (3 times, 400-1000L). The combined organic extracts werewashed with aqueous Na₂CO₃ (4 times, 522 L, 18% w/w 2.5 vol), water (523L; 2.5 vol), and 10% aqueous NaCl (314 L, 1.5 vol). The organic layerwas concentrated in vacuo to afford methyl(2S)-2,4-dimethyl-4-nitro-pentanoate as a mobile yellow oil (>98% ee,94.4 kg; 45% yield).

Step 3: Synthesis of (3S)-3,5,5-trimethylpyrrolidin-2-one

A 20 L reactor was purged with N₂. The vessel was charged sequentiallywith DI water-rinsed, damp Raney® Ni (2800 grade, 250 g), methyl(2S)-2,4-dimethyl-4-nitro-pentanoate (1741 g, 9.2 mol), and ethanol(13.9 L, 8 vol). The reaction was stirred at 900 rpm, and the reactorwas flushed with H₂ and maintained at ˜2.5 bar. The reaction mixture wasthen warmed to 60° C. for 5 hours. The reaction mixture was cooled andfiltered to remove Raney nickel, and the solid cake was rinsed withethanol (3.5 L, 2 vol). The ethanolic solution of the product wascombined with a second equal sized batch and concentrated in vacuo toreduce to a minimum volume of ethanol (˜1.5 volumes). Heptane (2.5 L)was added, and the suspension was concentrated again to ˜1.5 volumes.This was repeated 3 times; the resulting suspension was cooled to 0-5°C., filtered under suction, and washed with heptane (2.5 L). The productwas dried under vacuum for 20 minutes then transferred to drying traysand dried in a vacuum oven at 40° C. overnight to afford(3S)-3,5,5-trimethylpyrrolidin-2-one as a white crystalline solid (2.042kg, 16.1 mol, 87%). ¹H NMR (400 MHz, Chloroform-d) δ 6.39 (s, 1H), 2.62(ddq, J=9.9, 8.6, 7.1 Hz, 1H), 2.17 (dd, J=12.4, 8.6 Hz, 1H), 1.56 (dd,J=12.5, 9.9 Hz, 1H), 1.31 (s, 3H), 1.25 (s, 3H), 1.20 (d, J=7.1 Hz, 3H).

Step 4: Synthesis of (4S)-2,2,4-trimethylpyrrolidine Hydrochloride

A glass lined 120 L reactor was charged with lithium aluminum hydridepellets (2.5 kg, 66 mol) and dry THF (60 L) and warmed to 30° C. Theresulting suspension was charged with(S)-3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over2 hours while maintaining the reaction temperature at 30 to 40° C. Aftercomplete addition, the reaction temperature was increased to 60-63° C.and maintained overnight. The reaction mixture was cooled to 22° C.,then cautiously quenched with the addition of ethyl acetate (EtOAc) (1.0L, 10 moles), followed by a mixture of THF (3.4 L) and water (2.5 kg,2.0 eq), and then a mixture of water (1.75 kg) with 50% aqueous sodiumhydroxide (750 g, 2 equiv water with 1.4 equiv sodium hydroxide relativeto aluminum), followed by 7.5 L water. After the addition was complete,the reaction mixture was cooled to room temperature, and the solid wasremoved by filtration and washed with THF (3×25 L). The filtrate andwashings were combined and treated with 5.0 L (58 moles) of aqueous 37%HCl (1.05 equiv.) while maintaining the temperature below 30° C. Theresultant solution was concentrated by vacuum distillation to a slurry.Isopropanol (8 L) was added and the solution was concentrated to neardryness by vacuum distillation. Isopropanol (4 L) was added, and theproduct was slurried by warming to about 50° C. MTBE (6 L) was added,and the slurry was cooled to 2-5° C. The product was collected byfiltration and rinsed with 12 L MTBE and dried in a vacuum oven (55°C./300 torr/N₂ bleed) to afford (4S)-2,2,4-trimethylpyrrolidine.HCl as awhite, crystalline solid (6.21 kg, 75% yield). ¹H NMR (400 MHz, DMSO-d6)δ 9.34 (br d, 2H), 3.33 (dd, J=11.4, 8.4 Hz, 1H), 2.75 (dd, J=11.4, 8.6Hz, 1H), 2.50-2.39 (m, 1H), 1.97 (dd, J=12.7, 7.7 Hz, 1H), 1.42 (s, 3H),1.38 (dd, J=12.8, 10.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J=6.6 Hz, 3H).

Part B: Preparation ofN-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(Compound I)

Preparation of Starting Materials:3,3,3-Trifluoro-2,2-dimethyl-propan-1-ol

A 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, acooling bath, an addition funnel, and a J-Kem temperature probe. Thevessel was charged with lithium aluminum hydride (LAH) pellets (6.3 g,0.1665 mol) under a nitrogen atmosphere. The vessel was then chargedwith tetrahydrofuran (200 mL) under a nitrogen atmosphere. The mixturewas allowed to stir at room temperature for 0.5 hours to allow thepellets to dissolve. The cooling bath was then charged with crushed icein water and the reaction temperature was lowered to 0° C. The additionfunnel was charged with a solution of3,3,3-trifluoro-2,2-dimethyl-propanoic acid (20 g, 0.1281 mol) intetrahydrofuran (60 mL) and the clear pale yellow solution was addeddrop wise over 1 hour. After the addition was complete the mixture wasallowed to slowly warm to room temperature and stirring was continuedfor 24 hours. The suspension was cooled to 0° C. with a crushedice-water in the cooling bath and then quenched by the very slow anddrop wise addition of water (6.3 ml), followed by sodium hydroxidesolution (15 weight %; 6.3 mL) and then finally with water (18.9 mL).The reaction temperature of the resulting white suspension was recordedat 5° C. The suspension was stirred at ˜5° C. for 30 minutes and thenfiltered through a 20 mm layer of Celite. The filter cake was washedwith tetrahydrofuran (2×100 mL). The filtrate was dried over sodiumsulfate (150 g) and then filtered. The filtrate was concentrated underreduced pressure to provide a clear colorless oil (15 g) containing amixture of the product 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol in THF(73% weight of product ˜10.95g, and 27 wt. % THF as determined by1H-NMR). The distillate from the rotary evaporation was distilled atatmospheric pressure using a 30 cm Vigreux column to provide 8.75 g of aresidue containing 60% weight of THF and 40% weight of product (˜3.5 g).The estimated total amount of product is 14.45 g (79% yield). 1H NMR(400 MHz, DMSO-d6) δ 4.99 (t, J=5.7 Hz, 1H), 3.38 (dd, J=5.8, 0.9 Hz,2H), 1.04 (d, J=0.9 Hz, 6H).

tert-Butyl 3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

A 50 L Syrris controlled reactor was started and jacket set to 20° C.,stirring at 150 rpm, reflux condenser (10° C.) and nitrogen purge. MeOH(2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol)were added and the reactor was capped. The reaction was heated to aninternal temperature of 40° C. and the system was set to hold jackettemp at 40° C. Hydrazine hydrate (1300 g of 55% w/w, 22.31 mol) wasadded portion wise via addition funnel over 30 min. The reaction washeated to 60° C. for 1 h. The reaction mixture was cooled to 20° C. andtriethylamine (2.483 kg, 3.420 L, 24.54 mol) was added portion wise(exothermic), maintaining reaction temp <30° C. A solution of Bocanhydride (di-tert-butyl dicarbonate) (4.967 kg, 5.228 L, 22.76 mol) inMeOH (2.860 L) was added portion wise maintaining temperature <45° C.The reaction mixture was stirred at 20° C. for 16 h. The reactionsolution was partially concentrated to remove MeOH, resulting in a clearlight amber oil. The resulting oil was transferred to the 50 L reactor,stirred and added water (7.150 L) and heptane (7.150 L). The additionscaused a small amount of the product to precipitate. The aqueous layerwas drained into a clean container and the interface and heptane layerwere filtered to separate the solid (product). The aqueous layer wastransferred back to the reactor, and the collected solid was placed backinto the reactor and mixed with the aqueous layer. A dropping funnel wasadded to the reactor and loaded with acetic acid (1.474 kg, 1.396 L,24.54 mol), then began dropwise addition of acid. The jacket was set to0° C. to absorb the quench exotherm. After addition (pH=5), the reactionmixture was stirred for 1 h. The solid was collected by filtration andwashed with water (7.150 L), and washed a second time with water (3.575L) and pulled dry. The crystalline solid was scooped out of the filterinto a 20L rotovap bulb and heptane (7.150 L) was added. The mixture wasslurried at 45° C. for 30 mins, and then distilled off 1-2 volumes ofsolvent. The slurry in the rotovap flask was filtered and the solidswashed with heptane (3.575 L) and pulled dry. The solid was furtherdried in vacuo (50° C., 15 mbar) to give tert-butyl5-oxo-1H-pyrazole-2-carboxylate (2921 g, 71%) as coarse, crystallinesolid. ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.98 (d, J=2.9 Hz,1H), 5.90 (d, J=2.9 Hz, 1H), 1.54 (s, 9H).

Step A: tert-Butyl3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate

A mixture of 3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (10 g, 70.36 mmol)and tert-butyl 3-hydroxypyrazole-1-carboxylate (12.96 g, 70.36 mmol) intoluene (130 mL) was treated with triphenyl phosphine (20.30 g, 77.40mmol) followed by isopropyl N-isopropoxycarbonyliminocarbamate (14.99mL, 77.40 mmol) and the mixture was stirred at 110° C. for 16 hours. Theyellow solution was concentrated under reduced pressure, diluted withheptane (100 mL) and the precipitated triphenylphosphine oxide wasremoved by filtration and washed with heptane/toluene 4:1 (100 mL). Theyellow filtrate was evaporated and the residue purified by silica gelchromatography with a linear gradient of ethyl acetate in hexane (0-40%)to give tert-butyl3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate (12.3 g,57%) as an off white solid. ESI-MS m/z calc. 308.13477, found 309.0(M+1)⁺; Retention time: 1.84 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.10(d, J=3.0 Hz, 1H), 6.15 (d, J=3.0 Hz, 1H), 4.18 (s, 2H), 1.55 (s, 9H),1.21 (s, 6H).

Step B: 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole

tert-Butyl3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-carboxylate (13.5 g,43.79 mmol) was treated with 4 M hydrogen chloride in dioxane (54.75 mL,219.0 mmol) and the mixture was stirred at 45° C. for 1 hour. Thereaction mixture was evaporated to dryness and the residue was extractedwith 1 M aqueous NaOH (100 ml) and methyl tert-butyl ether (100 ml),washed with brine (50 ml) and extracted with methyl tert-butyl ether (50ml). The combined organic phases were dried, filtered and evaporated togive 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (9.0 g, 96%)as an off white waxy solid. ESI-MS m/z calc. 208.08235, found 209.0(M+1)⁺; Retention time: 1.22 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.91(s, 1H), 7.52 (d, J=2.2 Hz, 1H), 5.69 (t, J=2.3 Hz, 1H), 4.06 (s, 2H),1.19 (s, 6H).

Step C: tert-Butyl 2,6-dichloropyridine-3-carboxylate

A solution of 2,6-dichloropyridine-3-carboxylic acid (10 g, 52.08 mmol)in THF (210 mL) was treated successively with di-tert-butyl dicarbonate(17 g, 77.89 mmol) and 4-(dimethylamino)pyridine (3.2 g, 26.19 mmol) andleft to stir overnight at room temperature. At this point, HCl 1N (400mL) was added and the mixture was stirred vigorously for about 10minutes. The product was extracted with ethyl acetate (2×300 mL) and thecombined organics layers were washed with water (300 mL) and brine (150mL) and dried over sodium sulfate and concentrated under reducedpressure to give 12.94 g (96% yield) of tert-butyl2,6-dichloropyridine-3-carboxylate as a colorless oil. ESI-MS m/z calc.247.01668, found 248.1 (M+1)⁺; Retention time: 2.27 minutes. ¹H NMR (300MHz, CDCl₃) ppm 1.60 (s, 9H), 7.30 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz,1H).

Step D: tert-Butyl2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate

To a solution of tert-butyl 2,6-dichloropyridine-3-carboxylate (10.4 g,41.9 mmol) and 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (9.0g, 41.93 mmol) in DMF (110 mL) were added potassium carbonate (7.53 g,54.5 mmol) and 1,4-diazabicyclo[2.2.2]octane (706 mg, 6.29 mmol) and themixture was stirred at room temperature for 16 hours. The creamsuspension was cooled in a cold water bath and cold water (130 mL) wasslowly added. The thick suspension was stirred at room temperature for 1hour, filtered and washed with plenty of water to give tert-butyl2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate(17.6 g, 99%) as an off white solid. ESI-MS m/z calc. 419.12234, found420.0 (M+1)⁺; Retention time: 2.36 minutes. ¹H NMR (400 MHz, DMSO-d6) δ8.44 (d, J=2.9 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H),6.26 (d, J=2.9 Hz, 1H), 4.27 (s, 2H), 1.57 (s, 9H), 1.24 (s, 6H).

Step E:2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylicAcid

tert-Butyl2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylate(17.6 g, 40.25 mmol) was suspended in isopropanol (85 mL) treated withhydrochloric acid (34 mL of 6 M, 201 mmol) and heated to reflux for 3hours (went almost complete into solution at reflux and started toprecipitate again). The suspension was diluted with water (51 mL) atreflux and left to cool to room temperature under stirring for 2.5 h.The solid was collected by filtration, washed with isopropanol/water 1:1(50 mL), plenty of water and dried in a drying cabinet under vacuum at45-50° C. with a nitrogen bleed overnight to give2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (13.7 g, 91%) as an off white solid. ESI-MS m/z calc. 363.05975,found 364.0 (M+1)⁺; Retention time: 1.79 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 13.61 (s, 1H), 8.44 (d, J=2.9 Hz, 1H), 8.39 (d, J=8.4 Hz,1H), 7.77 (d, J=8.4 Hz, 1H), 6.25 (d, J=2.9 Hz, 1H), 4.28 (s, 2H), 1.24(s, 6H).

Step F:2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide

2-Chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (100 mg, 0.2667 mmol) and CDI (512 mg, 3.158 mmol) were combined inTHF (582.0 μL) and the mixture was stirred at room temperature.Meanwhile, 1,3-dimethylpyrazole-4-sulfonyl chloride (62 mg, 0.3185 mmol)was combined with ammonia (in methanol) in a separate vial, instantlyforming a white solid. After stirring for an additional 20 min, thevolatiles were removed by evaporation, and 1 mL of dichloromethane wasadded to the solid residue, and was also evaporated. DBU (100 μL, 0.6687mmol) was then added and the mixture stirred at 60° C. for 5 minutes,followed by addition of THF (1 mL) which was subsequently evaporated.The contents of the vial containing the CDI activated carboxylic acid inTHF were then added to the vial containing the newly formed sulfonamideand DBU, and the reaction mixture was stirred for 4 hours at roomtemperature. The reaction mixture was diluted with 10 mL of ethylacetate, and washed with 10 mL solution of citric acid (1 M). Theaqueous layer was extracted with ethyl acetate (2×10 mL) and thecombined organics were washed with brine, dried over sodium sulfate, andconcentrated to give the product as white solid (137 mg, 99%) that wasused in the next step without further purification. ESI-MS m/z calc.520.09076, found 521.1 (M+1)⁺; Retention time: 0.68 minutes.

Step G:N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

2-Chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide(137 mg, 0.2630 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloridesalt) (118 mg, 0.7884 mmol), and potassium carbonate (219 mg, 1.585mmol) were combined in DMSO (685.0 μL) and the mixture was heated at130° C. for 16 hours. The reaction was cooled to room temperature, and 1mL of water was added. After stirring for 15 minutes, the contents ofthe vial were allowed to settle, and the liquid portion was removed viapipet and the remaining solids were dissolved with 20 mL of ethylacetate and were washed with 1 M citric acid (15 mL). The layers wereseparated and the aqueous layer was extracted two additional times with15 mL of ethyl acetate. The organics were combined, washed with brine,dried over sodium sulfate and concentrated. The resulting solid wasfurther purified by silica gel chromatography eluting with a gradient ofmethanol in dichloromethane (0-10%) to giveN-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(72 mg, 41%) as a white solid. ESI-MS m/z calc. 597.2345, found 598.3(M+1)⁺; Retention time: 2.1 minutes. ¹H NMR (400 MHz, DMSO) δ 12.36 (s,1H), 8.37 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 6.93(d, J=8.2 Hz, 1H), 6.17 (d, J=2.8 Hz, 1H), 4.23 (s, 2H), 3.81 (s, 3H),2.56 (d, J=10.4 Hz, 1H), 2.41 (t, J=8.7 Hz, 1H), 2.32 (s, 3H), 2.18 (dd,J=12.4, 6.1 Hz, 1H), 1.87 (dd, J=11.7, 5.5 Hz, 1H), 1.55 (d, J=11.2 Hz,6H), 1.42 (t, J=12.0 Hz, 1H), 1.23 (s, 6H), 0.81 (d, J=6.2 Hz, 3H).

Alternative Steps F and G: Alternative Step F:2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinamide

To a suspension of2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylicacid (20.0 g, 53.89 mmol) in THF (78.40 mL) was added solidcarbonyldiimidazole (approximately 10.49 g, 64.67 mmol) portion wise andthe resulting solution was stirred at room temperature (slight exothermfrom 18-21° C. was observed). After 1 h, solid1,3-dimethylpyrazole-4-sulfonamide (approximately 11.33 g, 64.67 mmol)was added, followed by DBU (approximately 9.845 g, 9.671 mL, 64.67 mmol)in two equal portions over 1 min (exotherm from 19 to 35° C.). Thereaction mixture was stirred at room temperature for 16 h. The reactionmixture was diluted with ethyl acetate (118 mL) and then HCl(approximately 107.8 mL of 2 M, 215.6 mmol). The phases were separatedand the aqueous phase was extracted with ethyl acetate (78 mL). Thecombined organics were washed with water (39.2 mL), then brine (40 mL),dried over sodium sulfate and concentrated. The resulting foam wascrystallized from a 1:1 isopropanol:heptane mixture (80 mL) to afford2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinamide(26.1 g, 93%) as a white solid. ESI-MS m/z calc. 520.0, found 520.9(M+1)⁺; Retention time: 1.83 minutes.

Alternative Step G:N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide(20.0 g, 38.39 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloridesalt) (approximately 14.36 g, 95.98 mmol), and K2CO3 (approximately26.54 g, 192.0 mmol) were combined in DMSO (80.00 mL) and1,2-diethoxyethane (20.00 mL) in a 500-mL flask with reflux condenser.The reaction mixture was heated at 120° C. for 16 h then cooled to roomtemperature. The reaction was diluted with DCM (200.0 mL) and HCl(approximately 172.8 mL of 2 M, 345.5 mmol); aqueous pH ˜1. The phaseswere separated, and the aqueous phase was extracted with DCM (100.0 mL).The organic phases were combined, washed with water (100.0 mL) (3×), anddried (Na2SO4) to afford an amber solution. The solution was filteredthrough a DCM-packed silica gel bed (80 g; 4 g/g) and washed with 20%EtOAc/DCM (5×200 mL). The combined filtrate/washes were concentrated toafford 22.2 g of an off-white powder. The powder was slurried in MTBE(140 mL) for 30 min. The solid was collected by filtration(paper/sintered-glass) to afford 24 g after air-drying. The solid wastransferred to a drying dish and vacuum-dried (40° C./200 torr/N2 bleed)overnight to afford 20.70 g (90%) of a white powder. ESI-MS m/z calc.597.2345, found 598.0 (M+1)+; Retention time: 2.18 minutes.

¹H NMR (400 MHz, Chloroform-d) δ 13.85 (s, 1H), 8.30 (d, J=8.6 Hz, 1H),8.23 (d, J=2.8 Hz, 1H), 8.08 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 5.98 (d,J=2.8 Hz, 1H), 4.24 (s, 2H), 3.86 (s, 3H), 3.44 (dd, J=10.3, 8.4 Hz,1H), 3.09 (dd, J=10.3, 7.8 Hz, 1H), 2.67-2.52 (m, 1H), 2.47 (s, 3H),2.12 (dd, J=12.3, 7.8 Hz, 1H), 1.70 (dd, J=12.4, 9.6 Hz, 1H), 1.37 (s,3H), 1.33 (s, 3H), 1.27 (s, 6H), 1.20 (d, 3H).

Alternative Synthesis of3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole

Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol

A reactor was loaded with toluene (300 mL) and3,3,3-trifluoro-2,2-dimethylpropanoic acid (30 g, 192.2 mmol), capped,purged under nitrogen. The reaction was set to control the internaltemperature to 40° C. A solution of Vitride (65% in toluene.approximately 119.6 g of 65% w/w, 115.4 mL of 65% w/w, 384.4 mmol) wasset up for addition via syringe, and addition was begun at 40° C., withthe target addition temperature between 40 and 50° C. The reaction wasstirred at 40° C. for 90 min. The reaction was cooled to 10° C. then theremaining Vitride was quenched with slow addition of water (6 mL). Asolution of 15% aq NaOH (30 mL) was added in portions, and solidsprecipitated half way through the base addition. Water (60.00 mL) wasadded. The mixture was warmed to 30° C. and held for at least 15 mins.The mixture was then cooled to 20° C. The aqueous layer was removed. Theorganic layer was washed with water (60 mL×3), and then washed withbrine (60 mL). The washed organic layer was dried under Na₂SO₄, followedwith MgSO₄. The mix was filtered through Celite, and the cake washedwith toluene (60.00 mL) and pulled dry. The product3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (22.5 g, 82%) was obtained asclear colorless solution.

Step 2: Preparation of 1-(tert-butyl) 4-ethyl3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate

A reactor was charged with 3,3,3-trifluoro-2,2-dimethylpropan-1-ol(17.48 g, 123.0 mmol) solution in toluene (250g), 1-(tert-butyl) 4-ethyl3-hydroxy-1H-pyrazole-1,4-dicarboxylate (30.0 g, 117.1 mmol), and PPh₃(35.33 g, 134.7 mmol). The reaction was heated to 40° C. DIAD (26.09 mL,134.7 mmol) was weighed and placed into a syringe and added over 10minutes while maintaining an internal temperature ranging between 40 and50° C. The reaction was then heated to 100° C. over 30 minutes. Afterholding at 100° C. for 30 minutes, the reaction was complete, and themixture was cooled to 70° C. over 15 minutes. Heptane (180.0 mL) wasadded, and the jacket was cooled to 15° C. over 1 hour. (TPPO begancrystallizing at ˜35° C.). The mixture stirring at 15° C. was filtered(fast), the cake was washed with a pre-mixed solution of toluene (60 mL)and heptane (60 mL) and then pulled dry. The clear solution wasconcentrated to a waxy solid (45° C., vacuum, rotovap). Crude1-(tert-butyl) 4-ethyl3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate(53.49g) was obtained as a waxy solid, (˜120% of theoretical massrecovered).

Step 3: Preparation of3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylic Acid

A solution of 1-(tert-butyl) 4-ethyl3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1,4-dicarboxylate(50.0 g, 131 mmol) in 2-methyltetrahydrofuran (500 mL) was prepared in areactor and stirred at 40° C. Portions of KOt-Bu (80.85 g, 720.5 mmol)were then added over 30 minutes. Addition was exothermic. After 2053.49g UPLC-MS showed complete removal of the Boc group, so water (3.53g, 3.53 mL, 196 mmol) was added drop-wise addition via syringe over 20min to keep the reaction temperature between 40-50° C. The mixture wasthen stirred for 17 hours to complete the reaction. The mixture was thencooled to 20° C. and water (400 mL) was added. The stirring was stoppedand the layers were separated. The desired product in the aqueous layerwas returned to the reactor and the organic layer was discarded. Theaqueous layer was washed with 2-Me-THF (200 mL). Isopropanol (50. mL)was added followed by dropwise addition of aqueous HCl (131 mL of 6.0 M,786.0 mmol) to adjust the pH to <3 while maintaining the temperaturebelow 30° C. The resulting solid was then isolated by filtration and thefilter cake washer with water (100 mL) then pulled dry until a stickycake was obtained. The solids were then dried under vacuum at 55° C. toafford 3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylicacid (23.25 g) as an off-white fine solid.

Step 4: Preparation of3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole

3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-4-carboxylic acid(1.0 equiv) was added to a reactor followed by DMF (6.0 vol, 2.6 wtequiv). The mixture was stirred at 18-22° C. DBU (0.2 equiv.) wascharged to the reaction mixture at a rate of approximately 45 mL/min.The reaction temperature was then raised to 98-102° C. over 45 minutes.The reaction mixture was stirred at 98-102° C. for no less than 10 h.The reaction mixture was then cooled to −2° C. to 2° C. overapproximately 1 hour and was used without isolation to make ethyl2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate.

Alternate Procedure for the Preparation of2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxylicAcid

Step 1. Ethyl2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate

A solution of ethyl 2,6-dichloronicotinate (256 g, 1.16 mol) and3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (242 g, 1.16 mol)in DMF (1.53 L) was treated with potassium carbonate (209 g, 1.51 mol)and DABCO (19.6 g, 174 mmol). The resultant suspension was stirredallowed to exotherm from 14 to 25° C. and then maintained at 20-25° C.with external cooling for 3 days. The suspension was cooled to below 10°C. when water (2.0 L) was added in a thin stream while maintaining thetemperature below 25° C. After the addition was complete, the suspensionwas stirred for an additional 1 h. The solid was collected by filtration(sintered-glass/polypad) and the filter-cake was washed with water(2×500-mL) and dried with suction for 2 h to afford water-damp ethyl2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate(512 g; 113% yield) as white powder which was used without further stepsin the subsequent reaction.

Step 2.2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)nicotinicAcid

The water-damp ethyl2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)nicotinate(455 g, 1.16 mol; assumed 100% yield from previous step) in EtOH (1.14L) and THF (455 mL) was stirred at ambient temperature (17° C.) when 1 MNaOH (1.16 L, 1.16 mol) was added. The reaction mixture exothermed to30° C. and was further warmed at 40° C. for 2 h. The solution wasquenched with 1 M HCl (1.39 L, 1.39 mol) which resulted in an immediateprecipitation which became thicker as the acid was added. The creamysuspension was allowed to cool to room temperature and was stirredovernight. The solid was collected by filtration (sintered-glass/polypad). The filter-cake was washed with water (2×500-mL). The filter-cakewas dried by suction for 1 h but remained wet. The damp solid wastransferred to a 10-L Buchi flask for further drying (50° C./20 torr),but was not effective. Further effort to dry by chasing with i-PrOH wasalso ineffective. Successful drying was accomplished after the dampsolid was backfilled with i-PrOAc (3 L), the suspension was heated at60° C. (homogenization), and re-concentrated to dryness (50° C./20 torr)to afford dry2-chloro-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1h-pyrazol-1-yl)nicotinicacid (408 g; 97% yield for two steps) as a fine, white powder. Theproduct was further dried in a vacuum oven (50° C./10 torr/N2 bleed) for2 h but marginal weight loss was observed. 1H NMR (400 MHz, DMSO-d6) δ13.64 (s, 1H), 8.49-8.36 (m, 2H), 7.77 (d, J=8.4 Hz, 1H), 6.26 (d, J=2.8Hz, 1H), 4.28 (s, 2H), 1.24 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ −75.2.KF analysis: 0.04% water.

Preparation of Form A of Compound I

The crystalline Form A of Compound I was obtained as a result of thefollowing synthesis. Combined2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide(108 g, 207.3 mmol), (4S)-2,2,4-trimethylpyrrolidine (Hydrochloridesalt) (77.55 g, 518.2 mmol), was combined with K₂CO₃ (143.2 g, 1.036mol) in DMSO (432.0 mL) and 1,2-diethoxyethane (108.0 mL) in a 1-L RBflask with a reflux condenser. The resulting suspension was heated at120° C. and was stirred at temperature overnight. Then the reaction wasdiluted with DCM (1.080 L) and HCl (933.0 mL of 2 M, 1.866 mol) wasslowly added. The liquid phases were separated, and the aqueous phasewas extracted with DCM (540.0 mL). The organic phases were combined,washed with water (540.0 mL) (3×), then dried with (Na₂SO₄) to afford anamber solution. Silica gel (25 g) was added and then the dryingagent/silica gel was filtered off. The filter-bed was washed with DCM(3×50-mL). The organic phases were combined and concentrated (40° C./40torr) to afford crudeN-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide(198.6 g, 160% theory) as an off-white solid. The solid was diluted withMTBE (750 mL), warmed at 60° C. (external temperature), and mixed to ahomogenous suspension. The suspension was cooled to 30° C. with stirringand the solid was collected by filtration, air-dried, and vacuum-driedto afford Compound I (111.1 g; 90%) as a fine, white powder.

The crystalline Form A of Compound I was also obtained through thefollowing procedure. A suspension of Compound I (150.0 g, 228.1 mmol) iniPrOH (480 mL) and water (120 mL) was heated at 82° C. to obtain asolution. The solution was cooled with a J-Kem controller at a coolingrate of 10° C./h. Once the temperature reached 74° C., the solution wasseeded with a sample of Compound I in crystalline Form A.Crystallization occurred immediately. The sample was cooled to ˜5° C.,let stir for 1 h, and then the solid was collected by filtration(sintered glass/paper). The filter-cake was washed with i-PrOH (75 mL)(2×), air-dried with suction, air-dried in a drying dish (120.6 g mostlydried), vacuum-dried (55° C./300 torr/N2 bleed) for 4 h, and then RTovernight. Overnight drying afforded 118.3 g (87% yield) of a whitepowder.

A suspension of Compound I (116 g, 176.3 mmol) in iPrOH (371 mL) andwater (93 mL) was heated at 82° C. to obtain a solution. The solutionwas cooled to 20° C. with a J-Kem controller at a cooling rate of 10°C./h. Once the temperature reached 74° C., the solution was seeded witha sample of Compound I in crystalline Form A. Crystallization occurredimmediately. Cooling was stopped at 20° C. and the mixture was stirredovernight. The solid was collected by filtration, washed with i-PrOH(2×75 mL), air-dried with suction, and vacuum-dried (55° C./300 torr/N2bleed) to afford Compound I, Form A (103.3 g) as a white powder.

Example 2: Synthesis of Compound II:(R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

Step 1: (R)-Benzyl2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoateand ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate

Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of benzyl2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol)and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate(7.23 g, 25.3 mmol) in DMF (N,N-dimethylformamide) (17 mL). The reactionwas stirred at 80° C. for 46 hours under a nitrogen atmosphere. Themixture was then partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate. The combined ethylacetate layers were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product, a viscous brown oil which contains bothof the products shown above, was taken directly to the next step withoutfurther purification. (R)-Benzyl2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate,ESI-MS m/z calc. 470.2, found 471.5 (M+1)⁺. Retention time 2.20 minutes.((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate,ESI-MS m/z calc. 494.5, found 495.7 (M+1)⁺. Retention time 2.01 minutes.

Step 2:(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol

The crude reaction mixture obtained in step (A) was dissolved in THF(tetrahydrofuran) (42 mL) and cooled in an ice-water bath. LiAlH₄ (16.8mL of 1 M solution, 16.8 mmol) was added drop-wise. After the additionwas complete, the mixture was stirred for an additional 5 minutes. Thereaction was quenched by adding water (1 mL), 15% NaOH solution (1 mL)and then water (3 mL). The mixture was filtered over Celite, and thesolids were washed with THF and ethyl acetate. The filtrate wasconcentrated and purified by column chromatography (30-60% ethylacetate-hexanes) to obtain(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-olas a brown oil (2.68g, 87% over 2 steps). ESI-MS m/z calc. 366.4, found367.3 (M+1)⁺. Retention time 1.68 minutes. ¹H NMR (400 MHz, DMSO-d6) δ8.34 (d, J=7.6 Hz, 1H), 7.65 (d, J=13.4 Hz, 1H), 6.57 (s, 1H), 4.94 (t,J=5.4 Hz, 1H), 4.64-4.60 (m, 1H), 4.52-4.42 (m, 2H), 4.16-4.14 (m, 1H),3.76-3.74 (m, 1H), 3.63-3.53 (m, 2H), 1.42 (s, 3H), 1.38-1.36 (m, 6H)and 1.19 (s, 3H) ppm. (DMSO is dimethylsulfoxide).

Step 3:(R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol

(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol(2.5 g, 6.82 mmol) was dissolved in ethanol (70 mL) and the reaction wasflushed with N₂. Then Pd—C (250 mg, 5% wt) was added. The reaction wasflushed with nitrogen again and then stirred under H₂ (atm). After 2.5hours only partial conversion to the product was observed by LCMS. Thereaction was filtered through Celite and concentrated. The residue wasre-subjected to the conditions above. After 2 hours LCMS indicatedcomplete conversion to product. The reaction mixture was filteredthrough Celite. The filtrate was concentrated to yield the product (1.82g, 79%). ESI-MS m/z calc. 336.2, found 337.5 (M+1)⁺. Retention time 0.86minutes. ¹H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=12.6 Hz, 1H), 6.76 (d,J=9.0 Hz, 1H), 6.03 (s, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 4.37-4.31(m, 3H), 4.06 (dd, J=6.1, 8.3 Hz, 1H), 3.70-3.67 (m, 1H), 3.55-3.52 (m,2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.

Step 4:(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

DMF (3 drops) was added to a stirring mixture of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid(1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1hour a clear solution had formed. The solution was concentrated undervacuum and then toluene (3 mL) was added and the mixture wasconcentrated again. The toluene step was repeated once more and theresidue was placed on high vacuum for 10 minutes. The acid chloride wasthen dissolved in dichloromethane (10 mL) and added to a mixture of(R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol(1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) indichloromethane (45 mL). The reaction was stirred at room temperaturefor 1 hour. The reaction was washed with 1N HCl solution, saturatedNaHCO₃ solution and brine, dried over MgSO₄ and concentrated to yieldthe product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+1)⁺.Retention time 2.05 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H),7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H),4.51-4.48 (m, 1H), 4.39-4.34 (m, 2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.69(t, J=7.6 Hz, 1H), 3.58-3.51 (m, 2H), 1.48-1.45 (m, 2H), 1.39 (s, 3H),1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm

Step 5:(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide(3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) wasadded followed by p-TsOH.H₂O (p-toluenesulfonic acid hydrate) (204 mg,1.1 mmol). The reaction was heated at 80° C. for 45 minutes. Thesolution was concentrated and then partitioned between ethyl acetate andsaturated NaHCO₃ solution. The ethyl acetate layer was dried over MgSO₄and concentrated. The residue was purified by column chromatography(50-100% ethyl acetate-hexanes) to yield the product. (1.3 g, 47%,ee >98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+1)⁺. Retentiontime 1.69 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s,1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.2Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.40 (dd,J=2.6, 15.1 Hz, 1H), 4.10 (dd, J=8.7, 15.1 Hz, 1H), 3.90 (s, 1H),3.65-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H),1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.

Example 3: Synthesis of Compound III:N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamidePart A: Synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic Acid

Step 1: 2-Phenylaminomethylene-malonic Acid Diethyl Ester

A mixture of aniline (25.6 g, 0.275 mol) and diethyl2-(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150°C. for 2 h. The mixture was cooled to room temperature and dried underreduced pressure to afford 2-phenylaminomethylene-malonic acid diethylester as a solid, which was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆) δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H),7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m,6H).

Step 2: 4-Hydroxyquinoline-3-carboxylic Acid Ethyl Ester

A 1 L three-necked flask fitted with a mechanical stirrer was chargedwith 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.100mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). Themixture was heated to 70° C. and stirred for 4 h. The mixture was cooledto room temperature and filtered. The residue was treated with aqueousNa₂CO₃ solution, filtered, washed with water and dried.4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a palebrown solid (15.2 g, 70%). The crude product was used in next stepwithout further purification.

Step 3: 4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid

4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) wassuspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 hat reflux. After cooling, the mixture was filtered, and the filtrate wasacidified to pH 4 with 2N HCl. The resulting precipitate was collectedvia filtration, washed with water and dried under vacuum to give4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5g, 92%). ¹H NMR (DMSO-d₆) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H),8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m,1H).

Part B: Synthesis ofN-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

Step 1: Carbonic Acid 2,4-di-tert-butyl-phenyl Ester Methyl Ester

Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solutionof 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et₃N (139 mL, 1000mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled inan ice-water bath to 0° C. The mixture was allowed to warm to roomtemperature while stirring overnight, then filtered through silica gel(approx. 1L) using 10% ethyl acetate-hexanes (˜4 L) as the eluent. Thecombined filtrates were concentrated to yield carbonic acid2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g,quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (d, J=2.4 Hz, 1H), 7.29 (dd,J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H),1.29 (s, 9H).

Step 2: Carbonic Acid 2,4-di-tert-butyl-5-nitro-phenyl Ester MethylEster and Carbonic Acid 2,4-di-tert-butyl-6-nitro-phenyl Ester MethylEster

To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl estermethyl ester (4.76 g, 180 mmol) in conc. sulfuric acid (2 mL), cooled inan ice-water bath, was added a cooled mixture of sulfuric acid (2 mL)and nitric acid (2 mL). The addition was done slowly so that thereaction temperature did not exceed 50° C. The reaction was allowed tostir for 2 h while warming to room temperature. The reaction mixture wasthen added to ice-water and extracted into diethyl ether. The etherlayer was dried (MgSO₄), concentrated and purified by columnchromatography (0-10% ethyl acetate-hexanes) to yield a mixture ofcarbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester andcarbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as apale yellow solid (4.28 g), which was used directly in the next step.

Step 3: 2,4-Di-tert-butyl-5-nitro-phenol and2,4-Di-tert-butyl-6-nitro-phenol

The mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl estermethyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl estermethyl ester (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before KOH(2.0 g, 36 mmol) was added. The mixture was stirred at room temperaturefor 2 h. The reaction mixture was then made acidic (pH 2-3) by addingconc. HCl and partitioned between water and diethyl ether. The etherlayer was dried (MgSO₄), concentrated and purified by columnchromatography (0-5% ethyl acetate-hexanes) to provide2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 steps) and2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol: ¹HNMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H),1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: ¹H NMR(400 MHz, CDCl₃) δ 11.48 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).

Step 4: 5-Amino-2,4-di-tert-butyl-phenol

To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g,7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was addedPd-5% wt. on activated carbon (900 mg). The reaction mixture was stirredat reflux for 2 h, cooled to room temperature and filtered throughCelite. The Celite was washed with methanol and the combined filtrateswere concentrated to yield 5-amino-2,4-di-tert-butyl-phenol as a greysolid (1.66 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H, OH),6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH₂), 1.27 (m, 18H); HPLC ret.time 2.72 min, 10-99% CH₃CN, 5 min run; ESI-MS 222.4 m/z [M+H]⁺.

Step 5:N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g,188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et₃N(63.0 mL, 451 mmol) at ambient temperature. The mixture becamehomogeneous and was allowed to stir for 10 min before5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in smallportions. The mixture was allowed to stir overnight at ambienttemperature. The mixture became heterogeneous over the course of thereaction. After all of the acid was consumed (LC-MS analysis, MH+ 190,1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) wasadded to the orange solid material to produce a slurry. The mixture wasstirred on a rotovap (bath temperature 65° C.) for 15 min withoutplacing the system under vacuum. The mixture was filtered and thecaptured solid was washed with hexanes to provide a white solid that wasthe EtOH crystalate. Et₂O (diethyl ether) was added to the solidobtained above until a slurry was formed. The mixture was stirred on arotovapor (bath temperature 25° C.) for 15 min without placing thesystem under vacuum. The mixture was filtered and the solid captured.This procedure was performed a total of five times. The solid obtainedafter the fifth precipitation was placed under vacuum overnight toprovideN-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide(38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH₃CN, 5 min run; ¹H NMR(400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87(s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J=7.7Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H),1.37 (s, 9H); ESI-MS m/z calc'd 392.21; found 393.3 [M+H]⁺.

Example 4: Preparation of Tablet Formulation 1 (“Tablet 1”)

The intragranular components in Table 5: Compound I, the soliddispersion comprising 80 wt % substantially amorphous Compound II and 20wt % HPMC (see PCT Publication No. WO 2015/160787, the entire contentsare incorporated herein by reference), the solid dispersion comprising80 wt % substantially amorphous Compound III-d, 19.5 wt % HPMCAS and 0.5wt % sodium lauryl sulfate, and excipients were passed through a sieveand blended. The SDD comprising 80 wt % substantially amorphous CompoundIII-d, 19.5 wt % HPMCAS and 0.5 wt % sodium lauryl sulfate was made inthe same manner as that for the SDD comprising 80 wt % substantiallyamorphous Compound III, 19.5 wt % HPMCAS and 0.5 wt % sodium laurylsulfate as described in PCT Publication No. WO 2015/160787. The blendwas granulated using a roller compactor and then milled. The milledmaterial was added to a bin blender along with sieved extragranularcomponents (microcrystalline cellulose and magnesium stearate) andfurther blended. The final blend was compressed into tablets containingthe amounts in Table 5.

TABLE 5 “Tablet 1” Comprising 100 mg Compound I, 50 mg Compound II and75 mg Compound III-d. Amount per tablet Ingredient (mg) Intra-granularCompound I 100.0 Compound II SDD (80 wt % 62.5 Compound II and 20 wt %HPMC) Compound III-d SDD (80 wt % 93.7 Compound III-d, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium 29.3Microcrystalline cellulose 80.5 Extra-granular Microcrystallinecellulose 117.1 Magnesium Stearate 4.9 Total 488.0

Example 5: Preparation of Tablet Formulation 2 (“Tablet 2”)

The intragranular components in Table 6: Compound I, the soliddispersion comprising 80 wt % substantially amorphous Compound II and 20wt % HPMC (see PCT Publication No. WO 2015/160787, the entire contentsare incorporated herein by reference), the solid dispersion comprising80 wt % substantially amorphous Compound III-d, 19.5 wt % HPMCAS and 0.5wt % sodium lauryl sulfate, and croscarmellose sodium were passedthrough a sieve and blended. The SDD comprising 80 wt % substantiallyamorphous Compound III-d, 19.5 wt % HPMCAS and 0.5 wt % sodium laurylsulfate was made in the same manner as that for the SDD comprising 80 wt% substantially amorphous Compound III, 19.5 wt % HPMCAS and 0.5 wt %sodium lauryl sulfate as described in PCT Publication No. WO2015/160787. The blend was granulated using a roller compactor and thenmilled. The milled material was added to a bin blender along with sievedextragranular components (microcrystalline cellulose and magnesiumstearate) and further blended. The final blend was compressed intotablets containing the amounts in Table 6.

TABLE 6 “Tablet 2” Comprising 100 mg Compound I, 50 mg Compound II and75 mg Compound III-d. Amount per Ingredient tablet (mg) Intra-granularCompound I 100.0 Compound II SDD (80 wt % 62.4 Compound II and 20 wt %HPMC) Compound III-d SDD (80 93.8 wt % Compound III-d, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium 22.3Extra-granular Microcrystalline cellulose 89.1 Magnesium Stearate 3.7Total 371.3

Example 6: Preparation of Tablet Formulation 3 (“Tablet 3”)

The components in Table 7: Compound I, the solid dispersion comprising80 wt % substantially amorphous Compound II and 20 wt % HPMC (see PCTPublication No. WO 2015/160787, the entire contents are incorporatedherein by reference), the solid dispersion comprising 80 wt %substantially amorphous Compound III-d, 19.5 wt % HPMCAS and 0.5 wt %sodium lauryl sulfate, microcrystalline cellulose, and croscarmellosesodium were passed through a sieve and blended. The SDD comprising 80 wt% substantially amorphous Compound III-d, 19.5 wt % HPMCAS and 0.5 wt %sodium lauryl sulfate was made in the same manner as that for the SDDcomprising 80 wt % substantially amorphous Compound III, 19.5 wt %HPMCAS and 0.5 wt % sodium lauryl sulfate as described in PCTPublication No. WO 2015/160787. Sieved magnesium stearate was added andthe mixture was further blended. The final blend was compressed intotablets containing the amounts in Table 7.

TABLE 7 Tablet “3” Comprising 100 mg Compound I, 50 mg Compound II and75 mg Compound III-d. Amount per Ingredient tablet (mg) Compound I 100Compound II SDD (80 wt % 62.5 Compound II and 20 wt % HPMC) CompoundIII-d SDD (80 93.7 wt % Compound III-d, 19.5 wt % HPMCAS, and 0.5 wt %sodium lauryl sulfate) Microcrystalline cellulose 140.9 CroscarmelloseSodium 25.6 Magnesium stearate 4.3 Total 427.0

Example 7. Dissolution Testing

Dissolution testing was performed using USP Apparatus II (paddle), in0.5% CTAB in 50 mM Acetate Buffer pH 4.5 dissolution media, followingUSP <711>. Samples were collected using an autosampler and filteredthrough 10 μm PVDF filters into HPLC vials for reverse phase HPLCanalysis. Dissolution results are shown in FIGS. 2A, 2B, and 2C.

Example 8. In Vivo Pharmacokinetic Study in Dogs

Male beagle dogs were fasted overnight for at least 8 hours and offeredfood 2 hours prior to dosing. Tablets were administered orally, andblood samples were collected pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 34,48, 72, and 96 hours post-dose. Compound I, Compound II, and CompoundIII-d in the plasma were quantified. Bioavailability was assessed withdose normalized AUC. Data are shown in FIGS. 3A, 3B, and 3C

Example 9: Preparation of Tablet Formulation 4 (“Tablet 4”)

The intragranular components in Table 8: Compound I, the soliddispersion comprising 80 wt % substantially amorphous Compound II and 20wt % HPMC (see PCT Publication No. WO 2015/160787, the entire contentsare incorporated herein by reference), the solid dispersion comprising80 wt % substantially amorphous Compound III, 19.5 wt % HPMCAS and 0.5wt % sodium lauryl sulfate, and excipients were passed through a sieveand blended (see PCT Publication No. WO 2015/160787, the entire contentsare incorporated herein by reference). The blend was granulated using aroller compactor and then milled. The milled material was blended withsieved extragranular components (microcrystalline cellulose andmagnesium stearate). The final blend was compressed into tablets andfilm coated to produce final tablets containing the amounts in Table 8.

TABLE 8 “Tablet 4” Comprising 100 mg Compound I, 50 mg Compound II and75 mg Compound III. mg per Material Name tablet Intra Granular CompoundI 100 Compound II SDD (80 wt % 62.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 93.8 Compound III, 19.5 wt % HPMCAS, and 0.5wt % sodium lauryl sulfate) Croscarmellose sodium 29.3 Microcrystallinecellulose 80.5 Extra Granular Microcrystalline cellulose 117.1 Magnesiumstearate 4.9 Total Core Tablet 488 Film coat 14.6 Total Coated Tablet502.6

Example 10. Dissolution Testing

Dissolution testing was performed using USP Apparatus II (paddle), in0.5% CTAB in 50 mM Acetate Buffer pH 4.5 dissolution media, followingUSP <711>. Samples were collected using an autosampler and filteredthrough 10 μm PVDF filters into HPLC vials for reverse phase HPLCanalysis. Dissolution results for Tablet 4 are shown in FIGS. 5A, 5B,and 5C.

Example 11: Preparation of Tablet Formulations 5-13 (“Tablets 5, 6, 7,8, 9, 10, 11, 12, and 13”)

Tablets 5, 6, 7, 8, 9, 10, 11, 12, and 13 comprising Compounds I, II,and III, and excipients as shown in Tables 9, 10, 11, 12, 13, 14, 15,16, and 17, respectively, can be prepared as shown above for Tablets 1,2, 3, and 4. The solid dispersion comprising 80% substantially amorphousCompound II and 20 wt % HPMC and the solid dispersion comprising 80 wt %substantially amorphous Compound III, 19.5 wt % HPMCAS and 0.5 wt %sodium lauryl sulfate can be prepared as shown in PCT Publication No. WO2015/160787, the entire contents are incorporated herein by reference).

TABLE 9 “Tablet 5” Comprising 100 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 100.0 Compound II SDD (80 wt % 62.5 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium 29.3Microcrystalline cellulose 80.5 Extra-granular Microcrystallinecellulose 117.1 Magnesium Stearate 4.9 Total 581.8

TABLE 10 “Tablet 6” Comprising 100 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 100.0 Compound II SDD (80 wt % 62.5 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose Sodium 22.3Extra-granular Microcrystalline cellulose 89.1 Magnesium Stearate 3.7Total 465.1

TABLE 11 “Tablet 7” Comprising 100 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Compound I 100Compound II SDD (80 wt % 62.5 Compound II and 20 wt % HPMC) Compound IIISDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS, and 0.5 wt % sodiumlauryl sulfate) Microcrystalline cellulose 140.9 Croscarmellose Sodium25.6 Magnesium stearate 4.3 Total 520.8

TABLE 12 “Tablet 8” Comprising 100 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Intra- Compound I100 granular Compound II SDD (80 wt % 62.5 Compound II and 20 wt % HPMC)Compound III SDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS, and 0.5wt % sodium lauryl sulfate) Croscarmellose sodium 40 Microcrystallinecellulose 110 Extra- Microcrystalline cellulose 160 granular Magnesiumstearate 6.7 Total Core Tablet 666.7 Film coat 20 Total Coated Tablet686.7

TABLE 13 “Tablet 9” Comprising 50 mg Compound I, 25 mg Compound II and75 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 50 Compound II SDD (80 wt % 31.3 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 93.8 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 20Microcrystalline cellulose 55 Extra-granular Microcrystalline cellulose80 Magnesium stearate 3.3 Total Core Tablet 333.3 Film coat 10 TotalCoated Tablet 343.3

TABLE 14 “Tablet 10” Comprising 50 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 50 Compound II SDD (80 wt % 62.5 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 34.3Microcrystalline cellulose 94.3 Extra-granular Microcrystallinecellulose 137.1 Magnesium stearate 5.7 Total Core Tablet 571.4 Film coat17.1 Total Coated Tablet 588.6

TABLE 15 “Tablet 11” Comprising 25 mg Compound I, 25 mg Compound II and75 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 25 Compound II SDD (80 wt % 31.3 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 93.8 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 17.1Microcrystalline cellulose 47.1 Extra-granular Microcrystallinecellulose 68.6 Magnesium stearate 2.9 Total Core Tablet 285.7 Film coat8.6 Total Coated Tablet 294.3

TABLE 16 “Tablet 12” Comprising 25 mg Compound I, 50 mg Compound II and150 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 25 Compound II SDD (80 wt % 62.5 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 187.5 Compound III, 19.5 wt % HPMCAS,and 0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 31.4Microcrystalline cellulose 86.4 Extra-granular Microcrystallinecellulose 125.7 Magnesium stearate 5.2 Total Core Tablet 523.8 Film coat15.7 Total Coated Tablet 539.5

TABLE 17 “Tablet 13” Comprising 12.5 mg Compound I, 25 mg Compound IIand 75 mg Compound III. Amount per Ingredient tablet (mg) Intra-granularCompound I 12.5 Compound II SDD (80 wt % 31.3 Compound II and 20 wt %HPMC) Compound III SDD (80 wt % 93.8 Compound III, 19.5 wt % HPMCAS, and0.5 wt % sodium lauryl sulfate) Croscarmellose sodium 15.7Microcrystalline cellulose 43.2 Extra-granular Microcrystallinecellulose 62.9 Magnesium stearate 2.6 Total Core Tablet 261.9 Film coat7.9 Total Coated Tablet 269.8

Example 12: Preparation of Tablet Formulation 14 (“Tablet 14”)

Tablet 14 comprising Compounds I, II, and III, and excipients as shownin Table 18 was prepared as shown above for Tablet 4. The soliddispersion comprising 80 wt % substantially amorphous Compound II and 20wt % HPMC and the solid dispersion comprising 80 wt % substantiallyamorphous Compound III, 19.5 wt % HPMCAS and 0.5 wt % sodium laurylsulfate were prepared as shown in PCT Publication No. WO 2015/160787,the entire contents are incorporated herein by reference).

TABLE 18 “Tablet 14” Comprising 50 mg Compound I, 25 mg Compound II and37.5 mg Compound III. mg per Component tablet Intragranular Compound I50.0 a solid dispersion comprising: 31.3 80 wt % substantially amorphousCompound II, and 20 wt % HPMC a solid dispersion comprising: 46.9 80 wt% substantially amorphous Compound III, 19.5 wt % HPMCAS, and 0.5 wt %sodium lauryl sulfate Croscarmellose sodium 14.6 Microcrystalinecellulose 40.2 Extragranular Microcrystaline cellulose 58.6 Magnesiumstearate 2.4 Total Core Tablet 244.0 Film coat 7.3 Total 251.3

Example 13. Dissolution Testing of Tablet 14

Dissolution testing of Compound I in Tablet 14 was performed using USPApparatus II in 1.8% Tween20 in 50 mM sodium phosphate buffer. Sampleswere collected and filtered through 10 μm PVDF filters for HPLCanalysis.

Dissolution testing of Compound II in Tablet 14 was performed using USPApparatus II in 0.2% SDS in 50 mM sodium phosphate buffer. Samples werecollected and filtered through 10 μm PVDF filters for HPLC analysis.

Dissolution testing of Compound III in Tablet 14 was performed using USPApparatus II in 0.4% SLS in 50 mM sodium phosphate buffer. Samples werecollected and filtered through 10 μm PVDF filters for HPLC analysis.

Dissolution results for Tablet 14 are shown in FIGS. 6A, 6B, and 6C.

Example 14: Assays for Detecting and Measuring F508del-CFTR ModulatorProperties of Compounds Membrane Potential Optical Methods for AssayingProperties of F508del-CFTR Modulators

An optical assay was employed to measure changes in membrane potentialto determine the CFTR modulator properties of compounds. The assayutilized fluorescent voltage sensing dyes to measure changes in membranepotential using a fluorescent plate reader (e.g., FLIPR III, MolecularDevices, Inc.) as a readout for increase in functional F508del in NIH3T3 cells. The driving force for the response was the creation of achloride ion gradient in conjunction with channel activation andconcurrent with compound treatment by a single liquid addition stepafter the cells had previously been loaded with a voltage sensing dye.

Assay Procedure

NIH3T3 mouse fibroblasts stably expressing F508del were used for opticalmeasurements of membrane potential. The cells were maintained at 37° C.in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1×pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 12,000 cells/well in 384-wellmatrigel-coated plates. For the correction assay, the cells werecultured at 37° C. for 18-24 hours and loaded with a voltage sensingdye. The cells were then activated and treated with Compound I. After18-24 hours, fluorescence from the voltage sensing dye in the cells wasmeasured to assess changes in the membrane potential as a read out forincrease in functional F508del CFTR in the NIH3T3 cells.

Using this method, Compound I had an EC₅₀ of less than 3 μM and a %Efficacy of ≥100% relative to Compound II.

Ussing Chamber Assay

Ussing chamber experiments were performed on polarized airway epithelialcells expressing F508del to further characterize the F508del modulatorsidentified in the optical assay above. Non-CF and CF airway epitheliawere isolated from bronchial tissue, cultured using methods well knownin the art, and plated onto Costar® Snapwell™ filters that wereprecoated with NIH3T3-conditioned media. After four days the apicalmedia was removed and the cells were grown at an air liquid interfacefor >14 days prior to use. This resulted in a monolayer of fullydifferentiated columnar cells that were ciliated, features that arecharacteristic of airway epithelia. Non-CF human bronchial epithelial(HBE) cells were isolated from non-smokers that did not have any knownlung disease. CF-HBE cells were isolated from patients homozygous forF508del (F508del/F508del-HBE) or heterozygous for F508del with adifferent disease causing mutation on the other allele.

HBE cells grown on Costar® Snapwell™ cell culture inserts were mountedin an Ussing chamber (Physiologic Instruments, Inc., San Diego, Calif.),and the transepithelial resistance and short-circuit current in thepresence of a basolateral to apical Cl⁻ gradient (I_(SC)) were measuredusing a voltage-clamp system (Department of Bioengineering, Universityof Iowa, IA). Briefly, HBE cells were examined under voltage-clamprecording conditions (V_(hold)=0 mV) at 37° C. The basolateral solutioncontained (in mM) 145 NaCl, 0.83 K₂HPO₄, 3.3 KH₂PO₄, 1.2 MgCl₂, 1.2CaCl₂), 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and theapical solution contained (in mM) 145 NaGluconate, 1.2 MgCl₂, 1.2CaCl₂), 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).

Ussing Chamber Assay Procedure

A basolateral to apical membrane Cl⁻ concentration gradient was set upas follows. Normal Ringer's solution was used on the basolateralmembrane, whereas apical NaCl was replaced by equimolar sodium gluconate(titrated to pH 7.4 with NaOH) to give a large Cl⁻ concentrationgradient across the epithelium. Compound I was added either to thebasolateral side 18-24 hrs prior to assay or to the apical side duringthe assay. Forskolin (10 μM) was added to the apical side during theassay to stimulate CFTR-mediated Cl⁻ transport. Chloride current wasmeasured to assess the increase in functional CFTR in the cell membrane.

In Table 20, the following meanings apply: EC50: “+++” means <2 uM; “++”means between 2 uM to 5 uM; “+” means between 5 uM to 25 uM. % Efficacy:“+” means <25%; “++” means between 25% and 100%; “+++” means >100%.

TABLE 20 HBE EC₅₀ HBE Compound (μM) Max Eff (%) Compound I +++ +++

Example 15

Compound I is a potent, efficacious, and selective next generation CFTRcorrector that works by facilitating the processing and trafficking ofF508del-CFTR protein to the cell surface, resulting in enhanced chloridetransport.

The combination of Compound I and Compound II resulted in more thanadditive improvement in CFTR processing and trafficking compared toeither CFTR corrector alone, suggesting that the two CFTR correctors actthrough different mechanisms of action, which act synergistically toincrease the amount of F508del-CFTR delivered to the cell surface.

In addition, the more than additive effect of the combination ofCompound I and Compound II on the processing and trafficking of CFTRsuggests that the two CFTR correctors act through different mechanismsto result in the delivery of more CFTR protein to the cell surfacecompared to either CFTR corrector alone.

The triple combination of Compound I, Compound II, and Compound IIIenhanced chloride transport more than dual combinations at mostconcentrations of Compound I Compound 1 was administered to male SpragueDawley rats as a single nominal intravenous (IV) dose of 3.0 mg/kg in asolution in 10% NMP, 15% EtOH, 35% PEG400, 10% Solutol, and 30% D5W.Compound 1 was also administered to male Sprague Dawley rats at singlenominal oral dose (PO) of 3 mg/kg as a solution in 5% NMP, 30% PEG400,10% TPGS, 5% PVP-K30 at 5 mL/kg dose volume.

The study design, sample tracking, data run design and individual plasmasample concentrations were stored using Watson LIMS software, Version7.4.2 (Thermo Scientific Inc, Waltham, Mass.). Plasma concentration-timeprofiles of Compound 1 in Sprague Dawley rats at scheduled (nominal)sampling times were analyzed by noncompartmental pharmacokinetic methodsusing PK function within Watson LIMS software, Version 7.4.2 (ThermoScientific Inc, Waltham, Mass.). Key pharmacokinetic parameters such as“area under the curve” (AUC), from the time of drug administration, timezero, extrapolated to infinity, clearance (CL), and Percent of oralbioavailability (% F) were determined. The AUC values were calculatedusing the linear trapezoidal rule.

In Table 21 below, Compound I is shown to have advantageous rat oralexposure (AUC) and oral bioavailability.

TABLE 21 Rat iv CL Rat PO Rat PO (mL/ AUC AUC/dose min/ (μg · hr/ (μg ·hr/mL/ Compound kg) mL) mg/kg) Rat % F Compound I 1.6 ± 0.4 23.5 ± 1.79.4 ± 0.7 84%

Other Embodiments

The foregoing discussion discloses and describes merely exemplaryembodiments of this disclosure. One skilled in the art will readilyrecognize from such discussion and from the accompanying drawings andclaims, that various changes, modifications and variations can be madetherein without departing from the spirit and scope of this disclosureas defined in the following claims.

1. A pharmaceutical composition comprising (a) 75 mg to 125 mg ofCompound I:

(b) a first solid dispersion comprising 25 mg to 75 mg of Compound II:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and (c) a second solid dispersion comprising 50mg to 100 mg of Compound III:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion.
 2. The pharmaceutical composition of claim 1,comprising 75 mg to 125 mg of Compound I; and wherein the first soliddispersion comprises 50 mg of Compound II; and the second soliddispersion comprises 75 mg of Compound III.
 3. A pharmaceuticalcomposition comprising: (a) Compound I:

(b) a first solid dispersion comprising 70 wt % to 90 wt % of CompoundII relative to the total weight of the first solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thefirst solid dispersion; and (c) a second solid dispersion comprising 70wt % to 90 wt % of Compound III relative to the total weight of thesecond solid dispersion:

and 10 wt % to 30 wt % of a polymer relative to the total weight of thesecond solid dispersion, wherein the the weight ratio of Compound I in(a):Compound II in (b):Compound III in (c) is in a range of 4:2:3-6. 4.(canceled)
 5. (canceled)
 6. (canceled)
 7. The pharmaceutical compositionof claim 1, wherein Compound I is Crystalline Form A.
 8. Thepharmaceutical composition of claim 7, wherein Compound I CrystallineForm A is in substantially pure form.
 9. The pharmaceutical compositionof claim 7, wherein Compound I Crystalline Form A is characterized by anX-ray powder diffractogram having a signal at at least three two-thetavalues chosen from 6.6±0.2, 7.6±0.2, 9.6±0.2, 12.4±0.2, 13.1±0.2,15.2±0.2, 16.4±0.2, 18.2±0.2, and 18.6±0.2.
 10. A method of treatingcystic fibrosis in a patient comprising orally administering to thepatient one or more of the pharmaceutical composition of claim
 1. 11.The method according to claim 10, wherein said patient having cysticfibrosis is chosen from patients with F508del/minimal functiongenotypes, patients with F508del/F508del genotypes, patients withF508del/gating genotypes, and patients with F508del/residual functiongenotypes.
 12. (canceled)
 13. (canceled)
 14. The pharmaceuticalcomposition of claim 3, wherein at least one of the first and secondsolid dispersions is a spray-dried dispersion.
 15. The pharmaceuticalcomposition of claim 3, wherein both of the first and second soliddispersions are spray-dried dispersions.
 16. The pharmaceuticalcomposition of claim 3, wherein said polymer in the first soliddispersion is hydroxypropyl methylcellulose; and said polymer in thesecond solid dispersion is hydroxypropyl methylcellulose acetatesuccinate.
 17. The pharmaceutical composition of claim 3, wherein: thefirst solid dispersion comprises 70 wt % to 85 wt % of Compound IIrelative to the total weight of the first solid dispersion, and thepolymer is hydroxypropyl methylcellulose in an amount of 15 wt % to 30wt % relative to the total weight of the first solid dispersion; and thesecond solid dispersion comprises 70 wt % to 85 wt % of Compound IIIrelative to the total weight of the second solid dispersion, 0.5% sodiumlauryl sulfate relative to the total weight of the second soliddispersion, and the polymer is hydroxypropyl methylcellulose acetatesuccinate in an amount of 14.5 wt % to 29.5 wt % relative to the totalweight of the second solid dispersion.
 18. The pharmaceuticalcomposition of claim 3, wherein the first solid dispersion comprises 80wt % of Compound II relative to the total weight of the first soliddispersion; and 20 wt % of hydroxypropyl methylcellulose relative to thetotal weight of the first solid dispersion.
 19. The pharmaceuticalcomposition of claim 3, wherein the second solid dispersion comprises 80wt % of Compound III relative to the total weight of the second soliddispersion; 0.5% of sodium lauryl sulfate relative to the total weightof the second solid dispersion, and 19.5 wt % of hydroxypropylmethylcellulose acetate succinate relative to the total weight of thesecond solid dispersion.
 20. The pharmaceutical composition of claim 3,further comprising one or more pharmaceutically acceptable excipientschosen from one or more fillers, disintegrants, and lubricants.
 21. Thepharmaceutical composition of claim 3, wherein: said fillers are chosenfrom microcrystalline cellulose, silicified microcrystalline cellulose,lactose, dicalcium phosphate, mannitol, copovidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose, ethylcellulose, starch, Maltodextrin, agar, and guar gum; said disintegrantsare chosen from croscarmellose sodium, sodium starch glycolate,crospovidone, corn or pre-gelatinized starch, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, and microcrystallinecellulose; and said lubricants are chosen from magnesium stearate,sodium stearyl fumarate, calcium stearate, sodium stearate, stearicacid, and talc.
 22. The pharmaceutical composition of claim 3, whereinCompound I is substantially crystalline, and wherein each of CompoundsII and III is independently substantially amorphous.
 23. Thepharmaceutical composition of claim 3, wherein the pharmaceuticalcomposition is a tablet or in the form of granules.
 24. Thepharmaceutical composition of claim 3, wherein the pharmaceuticalcomposition further comprises microcrystalline cellulose; croscarmellosesodium; and magnesium stearate.
 25. The pharmaceutical composition ofclaim 3, wherein the pharmaceutical composition comprises 15 wt % to 45wt % of microcrystalline cellulose relative to the total weight of thepharmaceutical composition; 1 wt % to 10 wt % of croscarmellose sodiumrelative to the total weight of the pharmaceutical composition; and 0.5wt % to 3 wt % mg of magnesium stearate relative to the total weight ofthe pharmaceutical composition.
 26. The pharmaceutical composition ofclaim 1, wherein the pharmaceutical composition comprises 80 mg to 120mg of Compound I.
 27. The pharmaceutical composition of claim 1, whereinthe pharmaceutical composition comprises 100 mg of Compound I; andwherein the first solid dispersion comprises 50 mg of Compound II; andthe second solid dispersion comprises 75 mg of Compound III.
 28. Asingle tablet having the following formulation: mg per Material Nametablet Intra Granular Compound I 100 Compound II SDD (80 wt % 62.5Compound II and 20 wt % HPMC) Compound III SDD (80 wt % 93.8 CompoundIII, 19.5 wt % HPMCAS, and 0.5 wt % sodium lauryl sulfate)Croscarmellose sodium 29.3 Microcrystalline cellulose 80.5 ExtraGranular Microcrystalline cellulose 117.1 Magnesium stearate 4.9 TotalCore Tablet 488 Film coat 14.6 Total Coated Tablet 502.6.


29. A single tablet having the following formulation: mg per Componenttablet Intragranular Compound I 50.0 a solid dispersion comprising: 31.380 wt % substantially amorphous Compound II, and 20 wt % HPMC a soliddispersion comprising: 46.9 80 wt % substantially amorphous CompoundIII, 19.5 wt % HPMCAS, and 0.5 wt % sodium lauryl sulfate Croscarmellosesodium 14.6 Microcrystaline cellulose 40.2 Extragranular Microcrystalinecellulose 58.6 Magnesium stearate 2.4 Total Core Tablet 244.0 Film coat7.3 Total 251.3.